Experience with oral morphine for cancer pain relief

130 Journal of Pain and SymptomManagement

Vol. 4 No. 3 September1989

Experience with Oral Morphine for Cancer Pain Relief S. Vijayaram, MD, Krishna Bhargava, MD, Ramamani, MD, Chandrasekhar, MD, Sudharshan, MD, Roshni Heranjal, MD and Bridget Lobo, RN Department of Anestheticsand Pain Relief, Kidwai Memorial Institute of Oncology, Bangalore, India

Abstract The authors report a prospective survey of 88 patients with cancer pain who were treated with oral morphine solution during a period of 140 days at the Pain Relief Unit, Kidwai Memorial Institute of Oncology, Bangalore. A high percentage of pain relief was achieved at the end of the first week of titrated therapy; relief was maintained at satisfactory levels throughout the study period in a majority of patients (86%). Interruption of oral morphine administration was necessitated by intractable vomiting in two patients. The majority of patients (65%) did not manifest any side efects, and app-op-iate medication successfully managed those who did. Oral morphine therapy for cancer pain offers effective pain relief with minimal side effects in the majority of patients. J Pain Symptom Manage 1989;4:130-134. Key Words Oral morphine, cancer pain, pain relief

Zntroductim At any given time, an estimated 300,000 patients with advanced cancer suffer from intractable pain in India. i At the Kidwai Memorial Institute of Oncology, Bangalore, an estimated 75% of patients present in an advanced stage of disease, and a majority of them seek pain relief during the course of treatment. With the recent availability of oral morphine at this center, there is a distinct change in the management of intractable cancer pain toward a more cost-efreprints requeststo: Dr. S. Vijayaram, Department of Anesthetics and Pain Relief, Kidwai Memorial Institute of Oncology, Bangalore029, India. Accepted fbr publication: September 12, 1988 Address

6 U.S. Cancer Pain Relief Committee, 1989 Published by Elsevier, New York, New York

fective, uniformly applicable, and efficient mode of pain relief. The use of oral morphine for cancer pain relief is a very well-established mode of treatment and has gained an important place in all pain relief centers, hospices, and home care units.lm8 The World Health Organization (WHO) is propagating this inexpensive and effective method for cancer pain relief in a threestep approach known as the analgesic ladder. The use of oral morphine is advocated if pain does not respond to a nonsteroidal antiinflammatory drug (step 1) or a weak narcotic (step 2).g The experience of many leading workers, including Twycross,2 Ventafiidda,8 and Hanks,5 has led to the development of a regimen of oral morphine titration on a 4 hourly basis. This

0885-3924t89lt3.50

Vol. 4 No. 3 September 1989

Oral Morphine for Cancer Pain

regimen also involves control of side effects with appropriate drugs.2p5*6,8 Having adapted the WHO guidelines for treatment of patients with cancer pain, we present an analysis of 88 patients treated with oral morphine solution during a period of 140 days beginning January, 1988.

Laxatives were ordered from the beginning of therapy. A simple, uniformly applicable criterion for assessment of pain relief was adopted. Patients were asked to express the percentage of pain relief on a “rupee scale” (1 rupee = 100 paise). The data for analysis were collected every day during the hospital stay and once more 10 days after discharge.

Organization and Methods Kidwai Memorial Institute of Oncology is one of the regional centers for cancer treatment and research that serves the state of Karnataka and the neighboring states of south India. Over 10,000 new cases are registered every year. On average, about 200 cases per mo are referred by various oncology units for pain relief. Oral morphine is dispensed to those patients who reside in and around Bangalore to enable satisfactory monitoring. Those found unsuitable are treated with sublingual buprenorphine and/or nerve block procedures. For initiation of oral morphine therapy, those patients who are step 2 nonresponders are hospitalized. Liquid morphine solution is administered on a 4 hourly regimen, and the dose is increased every 24 hr to achieve pain control. Morphine solution is dispensed as an antibacterial solution in concentrations varying from 2.5 mg/5 mL to 200 mg/5 mL by the pharmacy attached to the Pain Relief Unit. In this prospective study, 88 patients who were step 2 nonresponders were inducted for oral morphine therapy. The mean age was 49.85 yr (SD = 12.34 yr). The majority of these patients were suffering from cancer of the uterine cervix (Table 1:). Morphine solution was administered every 4 hr. Titration was carried out every 24 hr. Patients were administered a nonsteroidal antiinflammatory drug for bony pain and other adjuvants as required for symptom control.

Results Satisfactory control of pain was achieved during the first week of therapy (Figure 1). The cumulative mean percentage of pain relief at the time of discharge was 85% (SD = 10%). Thereafter during the follow-up, satisfactory control of pain was maintained at 74%-82% (SD = 1 l%- 13%) on the rupee scale in the majority of patients. Satisfactory control of pain could not be achieved in eight cases (pain relief less than 40%). The reasons for termination of oral morphine treatment are shown in Table 2. It can be observed that only four cases were under evaluation on the 140th day of the study. Most patients entered into the study expired during the follow-up period. Nineteen patients were lost to follow-up. At their last visit to our clinic, the average pain relief in the latter group was 79% on the rupee scale. The mean daily dose to achieve satisfactory control of pain at the time of discharge was 31 mg (SD = 21 mg) administered every 4 hr (mean daily dose of 184 mg). The requirement for oral morphine in patients below 55 yr of age was greater than those above 55 yr of age. During follow-up, patients required a steady increase in the dose of oral morphine (Figure 2). Among those treated, the hours of sleep increased by 2-6 hr from the mean value of 5 hr at the beginning of treatment. The majority of Table 1

Clinical Diagnosis Ca cervix Head and neck Ca breast Ca rectum Ca pancreas Ca stomach Ca prostrate with bony secondaries Ca ovary

28 15 12 7 6 4 3

1

131

Ca oesophagus Ca lung Retroperitoneal tumor Ca thyroid Multiple myeloma with bony pain Osteogenic sarcoma Unknown primary with skeletal metastasis

132

Vijayaram

; .-

90

1

80

et al.

Journal

of Pain and Symptom Management

-4) -5 70 E

;

Number

60

of

(n-9)

patients

20 10

0

I

I

I

I

20

40

60

80

I 100

Number Fig. 1. Percentage

of pain relief

during

In our population, oral morphine achieved satisfactory control of pain in 80 of 88 (91%) of patients. Of those who did not obtain satisfactory pain relief, the majority had lymphoedema secondary to disease. Hence, it is possible that

Table 2 and Cause of Inten-uptiorA’ermination

l-20

6 5

21-40

41-60 61-80 81-100 101-120

10

4 5 2 4

121-140 operated.

iPatient refusal. pain

relief

days

of Days of Oral Morphine Therapy Alive

*Inadequate BVomiting.

of

oral morphine may be less effective in pain from this complication. The requirement for morphine gradually increased during the follow-up, which can be explained on the basis of progressive disease and appearance of new areas of pain,‘O as well as classical tolerance. Similar to other reports,” the requirement curve showed a plateau after the 80th day. The clear difference in the morphine requirement observed between younger and older patients is in accordance with the literature demonstrating reduced morphine clearance in older group of patients.‘* The average pain relief at the time of discharge in this population was 85% on the rupee

Di.wxkon

*Patient

140

140 days follow-up.

patients had no side effects at the time of discharge, as well as during the follow-up. In the rest, the incidence of side effects, such as itching, constipation, dry mouth, and drowsiness, is shown in Figure 3. Oral morphine therapy could not be continued because of vomiting in two cases.

Number

I

I

120

(2 cases).

Interruption

Expired

1*

13

11

4 2 2 2 3

5 2

-

1

-

4$8 1t

-

Lost

for Follow-up

-

1

A Publication

of the World

International

Health

Organization

Ccnt~for

Symptom

Evaluation,

Madison,

Wisconsin,

USA

Volume

3, No. 3 -Scptexnbcr

1989

Experts Call for WHO Support of Palliative Care

GENEVA, Ss - In July 1989, the world Health Organization (WHO) convened an eight-day Expclt commit Meeting on cancer Pain Rdief and Active Suppmtive Care. A nine-membaexpert IxanelwascalIedupontoexamine issues related to cancer pain and other common-symptom,andtomakc pmcticaI t-zOmtWndations for implementation worldwide At present, about 7 million new cancer patientsarediagnosedeveryyear,andabont 5 million people die of canccr. Slightly morethanbalfofthesencasesaleinthe deve.lopingcounuiee,. RevaIencedataindicatethat,atthcpresenttimc,thereareahout

14 million people living with cancer. Despite aII the maja advances m& thmugh research, two-thirds of cancer p&.nts in indusbialiicountriesdieoftheirdisease. In the d.eveIoping colmhies, the figure is much higher. TbeComtnittecagtecdthat’formanyyears to come, before p-ewltion, c&y diagnosis and curative tseamem have maxhnum impact, and before enough health facilities andtraincdbealthurrew~areavaiIable, active supportive are will be the only realistic and humme vh for many ULIlca patients.” lllc expcm mxed that a colrpervative e&mate of at least 4 million pti&SpresentlySUff~-painaad that“nod&gwooldhaveagwaterimpad onthequlityoflifcofthesepatientsthan disseminatingandimplcmentingthcknowledge that exists about pin and symptom COtlUOI.”

Collaborating

They recommended that WI-IO% existing cancer pain relief pmgtam be expand& to enalmpBss the management of other probhms aftlicting dying cancer patients and theirfamilies. Thiscanbcachievcdthmugh WI-IO’s suppmt of the concept of palliative cate,whichiotcgratescancerpainreliefinto a comprehensive approach to care at all stages of cancer. Reviewing the fioan&l rcsoallocatedtocancercare,theCommitteenc4ed that most of the rcsouws are allocated for curative treatments at arclatively high cost but with limited effects. Quality of life sod comfoti before death could be considerably improved through the appkation of current knowledge on palliadve care. All too often palliative care is ignored or seen as something that canes at the very end of the list of treatment options, a type of “waste paper basket” alternative. Instead, palliative care needstobeseenasanintegmlpartofcaocer care in both industrialized and developing counties. Curative and palliative cate arc not ncccssarily mutually exclusive for most cancer patients. The quality of life of these patientswouldbebeaxiftheyhadaccessto pliative cart IXnn the start. Drug Thompy Endoiwd ‘IheCommittecrcviewedthcWHOMcthod for Relieving Cancer Pain and concurred that,ifwedwnwtly,dmgsuxnmonlyused foKanccrpainrcmaintllc maiostayofcancerpainmanagementinahighpcrccntageof patients. ConhoOed singIedosezMies have demonstmtedthesafetyandeffi~dtheae dmgsaml certaincombinations ofthem All

of the dmgs ax not available in every coontry. Wherethisisthecase,theuseofthc drugs in the same class and of compamble efficacy is stmngIy advocated.

nxnphine and other opioids arc available for use by cancer pain patients and other patients who need them.

Mmagement QobidAv~ lX.wwsed In addition, the Committee exam&d the current status of opioid availability worldwide, especially morphine. It noted that the gI~morphi~~Oll~OSll1972

and 19I+7 ioaeascd by about 2.5 times. However, most of the increase has conx from 1984 onwards - the period in which wHohasbecncmphasizingthatdNg~tmen& including morphine, is the mainstay of cancer pain maoagcment. Ah, the increase inmnphineuseisrcstricted to 10 counhies. Namely, they are.

of C%her Symptom Formost cancer patients, pain is but one of seved symptoms. The Expert Committee examined psychogical and spiritual aspc& of care, as well as ethical considaatioos. parallel to the WHO method for relieving cancm pain, the committee also outlined simple, pragmatic guidelines for the management of many common symptoms suffered by caoca patients. ‘Ihcsc symptoms include mouth care, anorexia, dysphagia, nausea and vomiting, consti~tiOn, anxiety,

Icehnd,UnitedKingdom,I&md,Dentnark, Norway, Sweden, New Zealand, AustmIia,

Canada, and USA. lo these ten atntrics, mo+incuschasincmasedbyfowtima since. 1979. In the rest of the world, consumption is unchanged. Further, the current consumption of mo@ine in the top ten countries accounts for 75 % of global usage. A total of 133 other countries, for which statistics are available, account for the reImining 25%. The Committee

reviewed

and endcmed a

practical guide to opioid availability which was prepared jointly by WHO and the International Narcotics Control Board, and is aimedatlxalthcarcworkcrs,administmtors implcmcoting cancer pain relief programs, and drug regulatory authorities. ‘Ii-is guide outlines the steps to be. taken to establish an opioid availabiiity system that ensures that

depression, and several others. Guidelines for the doing of nurses in @liativecarepmposedbytheIntemational SccictyofNwsesinCaocerCarewasendomed as a model for other teaching progratns for other health professions. Schedukd to be plblished in the sping of 1990, the Committee’s report will include guidelii on cancer pain management, opioid availabilhy, management of other synqmms, and a model teach& program. Dr. Jan Stjem2.w~ Chief of the cancer Unit, commented that the Committee membm did an outstand@ job. “WHO die.5 on international expert.5 out in the battlefield who deal with cancex patients every day. When the practid guidelines they have drawn up arc made widely available to health care worh, it wiIl make a major impact gIobaUy.” 0

PharmacologyRounds

International Lqpl Issues Victories and Losses on the Cancer Pain Front

PsychotrOpic Adjuvaut Analgesic Drugs for Cancer Pain William

Breitbart,

Psychotropic drugs are now being utilii as adjuvants in the management of many c--relatisym@msmpoms. AntidepIrssants, psychostimulants, neurol@w and alLP iolytics are being prescribed for the control of chemotherapy-induced nausea and “Omiting, in the management of psychiatric complications of cancer and as adjuvant analgesics in the treatment of cpain. AlthougJ~ 80% of cancer patients receive a psychotmpic dmg, these medications are dramatically underutilized, especially as adjuvant analgesics and in the management of psychological distress. For example, while the prevalence of major depression is appoximately &lS%,only I-3Xofcancer patients receive an antidepressant. Psychotropic dmgs may be I#uticularly underutilized in patients with cancer pin. In addition to the pain itself, these patients are at increased risk for developing psychi&iccomplications. A survey perfamed by the Psychological Collaborative Oncology Group de&mined that 39% of patients who received a psychiatric diagnosis had significantpaincompwxlto 19% inthegroupthat hadno psycbiahicdiagnosis. ‘llxpsychiattic disorders seen in cancer pain patients were predominantly adjustment disorders with depressed mood (69%) and major depression (15%). Thus, cancc~ patients with pain have the mosttogainfromtheappmpriateuseof psychotropic drugs. Not only can these agentsbenefitdepwssion,anxictyacddelirium, but they have unique adjuvant analgesic pperties. Psychiatrists are often the most experienced in the clinical use of these drugs and can play an @ortaM role in assisting pin control. Table 1 lists the various psychotropic medications with analgesic pmperties, their routes of sdmini-

MD

Robert

snation, and theii appmximate ages.

daily dos-

Antidepn?55ants Tricyclic antidepressants (imipramine, amihiptyline, doxepin, clomipmmine) we effective adjuvants in cancerpein. They act onanumbxof ncsmtmmmim and their receptors; some investigators believe that their activity as potent semtonergic agents (semtoninre+ke-blockers)mediitheii analgesic propaties. In a placebo controlled. double-blind study ofimipamineinchmniccancerpain,Walsh demmsaated that im@amine had malgesic effects independent of its mood effe&, and was a potent co-analgesic when used along with morphine. Othaamidepmssantshavenotbeenproven to be analgesic in cancer pain patients, but may be use&l in selected patients. These

T Angarola,

I-mere

have been some significant successes mrccentmonthsinovexomingrezdand peatxivd legal barrios to effective cancer Fairmmagement. unfcmunate ly, over that mke period seveml statcs have impcecd qulatory restrictions on the availability of )pioid analgesics and other essential drugs hat will clearly result in fewer pain medicaions being presaibed for cpatients.

this July, representatives from 24 states tltendcd the National Meeting for State hcer Fain Initiatives in Madison, Wis:onsin. As described more fully elsewhere n this issue, this meeting allowed the paricipants to sham experiences and to de relop strategies on ways to encourage the lppro@te use of analgesics and adjuvant hugs in treating cancef pain while preventng the diversion of these substances for llicit purpoxs. The participants adopted a

f3=-cm!Y,P.4

WorthRepeating Edited by Russell

K. Portenoy,

MD

Use of Methylphenidate as an Adjuvant to Narcotic Aualgesics in Patients with Advanced Cancer llzis column is adapted&m nn original article by Eiuanio Bnrera, MD & al. published in the Journal of Pain and Symptom Mhagemmt 1989:4:3-h reduction in narcotic dew had been aied, Amphetamines have been suggested to be use&l adjuvant agents in human and animal models. our group has cor&cted two jcuble-blind hials of ma&&l and methylphenidate (I!@ as adjuvaot drugs in patients receiving narcotic analgesics for the reatment of cancer pain. Both trials have ruggestedthat~nederivativescan iecrmedc-inducedsomnolencewhile mhancing analgesia. In this report, we iescribetheclinicaluseof~~~~tients rested by our group between 1984 and 1987.

uimts andMetM Behvcen October 1984 and July 1987,50 latients were txated with MP by our gmup. 4U patients had pain due to advanced canxr, and all were receiving oral narcotic analgesics. The IXIKC&C analgesics were morphine (16 -1, WdnrmorFhone (11 cases), oxyccdon.z (10 cases), codeii (8 cases),slow-releasemorphine(3cases),aud levmphanol(2 cases). None of the @ems had arterial hypetension, heart disease, pCpiCUlLX~OFdiZ?betes,andllO~had~

history of drug dependence, alcoholism, bfain metastasea, or psychiatric disoers. lbedailylIaK&icd(Tablel)~haoslatedintoequivalentdoseofmorphiwusing standard tables. All ptients continued on thesamctypeanddoseofnarcoticsaRer aming MP. F%tients were cotidered eligible for Mp when they complained of severe somn+ lence at the minimal dose of narcotics reluti for adequate analgesia. In all cases.

but had resulted in recurrent pain. ReSdtS

Methylphenidate was started at a dose of 10 mgat8a.m.adSmgatnoun. After24hr of treatment, hvo patients (4%) had to discontinue the drug because of toxicity. One patient developed hallucinations and one manifested a paranoid-aggressive reaction. Bothcaswimpmvedwithin24hrofdiscontinuation of MP. The remaining 48 patients were evahmble for response, and 44 (91%) repomzd improvement in somnolence after 48 hr of treatment. These patients continued on MP for an average of 39 520 days. Tination of dose was done by assessing somnolence and restlessness. Four patients who repnted no improvement after 48 hr on MP diwmtiw ued the treatment. InitialandIn.&maldosesofnarcoticsand hP,andtoxicitytoMParesmmwizedin Tablel. InaUcaw,aoxi~oraervousness wasmanagedbydecmasingthedose. Table 1 RtmltsdTomty

Esq.

consensus document which calls for these newlyformedcancerpinitiativestowxk with legislatures and regulatory agencies to changeanylawsortegulationsthatint&ere with the medical use of narcotics. The State of Wisconsin has shown that the “War on Drugs” need not result in cancer patients being made the victim5 of this suuggle. Active implementation of the meeting’s recommendations will go a long way toward.s identifying and removing any legalbarrierstopmperpainreliefinotber states. WHO Gmeer lJnWZNCB Study The World Health Organimtion (WHO) Cancer Unit has taken a strong l-hip role in highlighting the undertreahnent of cancer pain in bath developed and develop ing countria, and in suggesting means of overcoming this pblem. WHO has fouud that many goveanments are co& that theinclweduseofmuwticsmaybeform of violation of the international drug control treaties. ?he International Narcotics Control Board (INCB) is the regulatory body set up by the Single Convention on Narcotic Drugs to monitor the licit movement of narcotics from pmducer to cocountties. Ihe Board’smandateisnotonlytopdmg diversion but also to ensure that these substances are awilable for medical paposes. The Single Convention itself states that natcotics are “bxliq)ensable” for the relief of pain and suffering. WHOandtheINCBhavejoinedforces reexltly to study the pmblem of the undmprscribing of narcotics for cancer pa& arid otherconditionsinova4o-~ghouttheworld. Oneoftheiigoalsistoinform govunments and health &-urJf~ionals that the drug confml tfeaties actually encmtage tbeuseofnarcoticsfor@nmwgenEnt. We now have the hvo most well respected international health organizatons working together to increase the medical use ofopiate% This will undoubtedly Esult in more and mare cancer ptients receiving n&cd pain relief. Yet for every domestic and i&mational advanceinpaincontml,thereseemstobea toun-ig set back. Mu&de Copy Pmmiptiott Pmgmm (MCPP) Some states have enacted laws that fcquire physicians to use multiple copy forms to prescribecertaindrugs,inchidingtbeopioid analgesics cancer patients need. One copy ofthisspecialpxscriptionfonngcestoa state enfagency. The swell states thathaveadopedthesesysfemspointwith pdetothcfacttbaqaimplementation, thmehasbeena5o%olgreater~in the pnwribing of drugs covered by the program. Typically, multiple copy prescription p gmmscoverschedulellsubstances. AUthe potent narcotics such as morphine, hydm morphone, oxycodone and fentanyl am included in this schedule. On January 1, seeLegalIssues,p.4

Satellite Teleconference Relays Cancer rain Information to Multi-Site Network in Europe PARIS, FRANCE -July 11,1989 - Hard on the heels of the WHO Expert Committee Meeting in Geneva, a pane.1of international expertstravelledtoPstotakepertinalive satellite teleconference organized by Medical Satellite, Panorama du M&kin, InterActiveEvent~andUPSA Laboratories. Ihe teleconference was linked up to 3 c0unhie=s, 4 sites in Switzerland, 3 sites in Belgium, and over 90 sites in France, reaching an audience of mainly doctors and nurses. Lasting two sod a half hours, the event was txansmitted interactively in English, French,

Flemish, Gexttunandltalian. Overan hour was devoted to questions from the audien~estinratedat8,OOO.Cenaaltothediscussion was the pxemi&e showing of the WHO video “Why Not Freedom t?vm cancer Pain.Panelists included: Dr. Kathleen M. Foley (USA), Dr. Neil R. MacJJonald (Canada), Ms.MargoMcCaffesy(USA),Dr.MicheleH.&ne Salamagne (France), Dr. Jan Stjemswtid (WHO, Geneva), Dr. Fumikam Takeda (Japan), Dr. Robert G. Twycmss (UK) sod Dr. Vittorio Ventafridda (kily). 0

Working Together to Relieve Cancer Pain MADISON, WISCONSIN - A national meeting tnuught together over 70 health professionals from 24 states, July 6-8, to share informdon about how to statt cancet pain initiatives. The meeting was organized by members ofthe WisconsinInitiative and 0ftheWHOCollaboratingollaboratingCenterforSymp tomEvaluatioo. It included~ntativea from Ivlaico, Australia, the American Cancer Society andtheNationaJInstitateon Drug Abuse. The Wisconsin Initiative is an education effottandWHOdemmmtionemonstrationprojectaimed at tellii health care professionals and Ibe generalpublicabouttheavailabilityofways to relieve cancer pain. Conferees recognized that many health professionals lack training in pain assessment, heatment, ad outcome evaluation. Pain comml is generally not a priority in healti care institutions. Furthermore, the treahnentofpainiswtapriorityinfederal or state cancer plans and budgets. Workshop discussions pointed out that patients, the public sod professionals are concerned about addiction to pain m&itines, although research shows that addictionisnotaproblemwhenoarcoticsareused to @eat cancer pain. Some state laws designed to deal with drug abuse hamper lbe medical use of narcotics to treat pain; some

Cancer Pain Relief-A

Cdl fo Action

We recommend that: l Cancer pain relief become a priority in the war against cancer. l Congress support neededresearch andprograms thatprovide cancerpain treatments that are available ROW to those who need them. l TheNational CancerAdvisory Boardreviewrhe cancerpainproblemand make recommendations for action. l A//patients with cancer and their families be informed that effective pain treatments are available and that the National Cancer Institute and the American Cancer Society develop education programs for patients, the public and professionals, andprovide readyaccess to cancerpain information and referral through existing toll free information services. l State cancer control plans include support forpain treatment andresearch as we// as for state cancer pain initiatives. l National organizations responsible for accrediting and providing health professional education take steps to assure that professional training includes pain assessment and treatment. l State laws and regulations that interfere with medical use of narcotics be identified and state cancer pain initiatives work with legislative and regulatory agencies for appropriate changes. l The ability to pay not be permitted to stand in the way of cancer pain relief. l Quality assurance activities to monitor cancer pain treatment in health care facilities be implemented. Excerpts~aPvlkyStatemntAdoptedU~

Meet&

for State Initiatks,

ybyFWticipanlsintbeNational

July 8,1989.

New Study Section Focuseson Children’s Paiu MADISON, WISCONSIN - Cancer pNin in children is a serious, undertreated problem that has received little attention in the pediahc or in the cancer pin literature. Recognizing this, the WHO Collaborating Center for Symptom Evaluation has formed a Children’s Section. ‘Ihereateanumberofteasons that efforts thatare.aimedatimprotigcancerpain management in adults may not spiuover and improve pain management in children. First of all, throughout the world, pediatric cancer is often treated in diffaent settings thancancerinadults. Asaresultadvancesin pain mnagetnentthat occurinadult centers areoftennottranspxedtotbechildsettings. Althoughchildttn’scancerpainappearsto beaswidespreadasadultcancerpain,itmay be of different types because of the differ-

enceindisease aodbecauseofdevelopmental factors. Finally, repeated studies in areas other than pain have shown that children are even -inadequately heated for various Fcdnfd conditions than are. adults. Although the reasons for this are not entirely clear, the fact that childrendo IWI show pain inthesamewayssadultsaadthefearofthe side effezts of strong analgesics may be importantintheneg&tofpainmanagementin children. The children’s Section will serve as a focal point to improve exchaogeofiiotmation and ideas on children’s cancer pain. workshops on pain manag-t in childmwillbeorgankd. The section will initiate and encourage research and development of cancer pain

A&ild’scanwrpabxAsrealasmaduit’s

patients with cancer who ask for pain relief aletmatedasaddiets. Health pfessionals in several state-s have begun cancer pain initiatives similar to Wisconsin’s to close the gap between the needs of the cancer patient and available pain treatments. F%tticipants agreed that it is essential to develop programs at the state levels because that is where most medical care is taught practiced, regulated and ptovided. Indeed, hundreds of volunteer physicians, nucses,pharmacistsaodotherIxakhpmfeasionals are ready to be mobilized, but there is little financial suppott to organize these efforts. Other counhies have recognized the severity of caM?er pain and have established nationalcancerpainpliciesandp~. Themwasaumsensu that in the U.S. stmngnationallcadexshipisneededtomake cancer pain relief a priority. Conference participanti voted mannmusly to endorse a policy statement, excerpts of which appear on the left. A completetextofthepolicystatemcntisavailable from: Wisconsin Cancer win Initiative, 3675 Medical Sciences Center, University of Wisconsin Medical School, 1300 University Avenue, Madison, Wisconsin 53706.0

pmgmms. Thesectionwillnotserveasa funding agency, but may be able to help obtain funding for projects. The tint research~jectwillbeginlater thisyearandwillbeanintemationalpractice survey on children’s cancer pain. Children’scancertmatmentcenterswillbe asked as to the extent and management of pin in the facility. Subsequent research my include patient surveys. Dr. Patrick McGmth, Professor and coordinator of Clinical Psychology at Dalhousie University in Halifax, Canada wiII act as section etor. Individuals wishing to join the section, amtrkute information or patticipate in the pmctke survey can contact Dr. MeGmth thmugh the Collaborating Ceoter, 646 WARP, 610 Walnut St., Madison, Wisconsin 53705, U.S.A. 0

1 with phantom limb pain or dcafferentation

min.

%&tic analgesics are the mainstay of 1plmrmacological interventions for cancer 1min. Them is however growing awareness Ihat psychotropic drugs, in ~ar!icular the mtidepressants, are us&I adjuvant analgericagentsinthemanageme”tofca”cerPai”. 1[“additionmanyofthcsedmgsareimpa; 1ant in the treatment of psychiatric compli,2io”s of cancer. Unfatnnately cancer 1p3tht.s with pai” arc most vulnaable to ruch problems as depression, anxiety and ,khium. For the clinician who wants to Iprovide Comprehensive management of (ancer Pain, familiarity with the indications mduscfulnessofpsychotro~icd~gswillbc 1most rewluding. 0 I

1References

1. Holla”d JC, Rowland J @is.) Handbook 9f PsychooncoZogy: Psychological Care of i :‘he Patient with Cnncer. Oxford University 1Press. New York, 1989. 2. Walsh TD. Controlled study of imiPram diminishing excessive sedation secom ine and morphine in chronic pain due to include tricyclic antidepressants, trazod~ne, l-llimwli” and fluoxetine. Mianseri” (not to narootic analgesics. Bruem et al. demonadvanced cancer (Abstmct) Proceedings of strated that a regimen of 10 mg methylpheavailable in the U.S.), is a patent semtonin 1the 22nd Annual ASCO Meeting, May 4-6, t-apt&e blocker with few adverse side ef- nklate with brcakf&t and 5 mg with lunch 1 1986: 231. feds. thus making it a” attractive choice a.3 significantly decreased sedation and poterr 3, BrGtbart W. Psychiatric managemen of an antidepressan or adjuvant analgesic. tiated the analgesic effect of narcotics ir I cancer pain. Olwer 1989;63: 23362342. Fhoxetine is only Rcently available in the ptients with canca pain. DextroamphetWilliam Breitban, MD, is Assistant Attendamine has been qmtcd to have additive U.S. and is a potent antidepressant which ing Psychianist, atMemorial Sloan-Ketteranalgesic effects when used with morphine hasbeenshowntohavea”algesicproperties in animal studies. Tmzodone has similar in postoperative pain. A strategy we have ing Gmcer Center, New York, New YonG antidepressant, semtonergic and analgesic found useful in treating cancer pain as-i. pqetties. TIE antidepressant meet com- ated with depression is to start a psychosLegalIssu~fromp.2 monly used in the maMgeme”t of cancer tallant (starting dose of 2.5 “lg of “l&h. ylphe”idatc at 8 a.m. and noon) and then tc pain are amihiptyli”e, imiplami”e, clomi1989, New York State also extended its pmmine, trazodone, and doxepin. There is add a tricyclic antidepressant after several MCFT to covex the bee class of no clear indication that any particular anti- days to help polong and potentiate the shori drugs. In June, the Depatmmt of Health effect of the stimulant. depressant is more effedive than tbc others, lqmted a” initial 70% to 80% reMon in although perhaps the most experience has prescriptions for these medicatio”s. These NtWVZ+iCS been accrued with amihiptyliie. Thechoice Methotrimeprazine is a phenothiazine thalt are the same substances that WHO considof drug often depends on the side effect profile, existbIg medical pmblems, the “a- is equianalgesic with morphine, has “one oi F ers to be “essential drugs” which should be available for medical purposes in every tme of dclressive symptoms if Iucscnt, and the opiate effects on gut motility and pmba countlyinthe world. ?heNewYorkHcaltb bly produces analgesia through alpha past response to speeitic a”tidepmssa”ts. admnergic blockade. In Patients who arr Department alsonotedasignificanticantincrease ScdatingdmgslikeamitiPtylincarehelpf”l in prescriptions for drugs not covered by the when insomnia compli~ the presence of opiate-tolerant, it offers a” alternative ap MCPP, drugs that, when used in place of the pain and depression on a cancer @ent. pmach in poviding analgesia by a “on ben7.odiazepines,are.lesseffcctiveandmae Anticholinergic ~x+xties of som of these opiate mechanism. It is adopamine blccke] dangerous. and so has antiemetic as well as anxiolytic drugs should also be. kept i” mid. Michigan and Indiana wilI soon impleTreahnent should be initiated with a small effects. This drug can pmduce sedation ant ment their own multiple copy pnscri@ion dose (e.g. amihiptylii 10 to 25 mg hs), hypotensionandshouldbegivencautiously programs. Wennf ommately can predict a especially in debilitated Patients, and in- Fluphenazioe in combination with TCA decrease in the use of schedule II opioid creased slowly by the same quantity cvcry 2 has been show” to be helpful in neuropathi( to 4 days. Frequent assessment of pain and pains. Halopcridol is the drug of choice ir analgcsicsinthcsestatesandanincreasein patients i” pain. side effects should be performed until a the management of delbimnor Psychoses ir the suffering of m The American Medical Association House beneficial effect is achieved. Maximal ef- cancer patients, and has clinical “scful”es! ofDelc.gateshasjust adopted areport which as a m-analgesic for cancer pain. fect as a” adjuvant analgesic may require concludes that not only am MCPF’s ‘inefco”tinuationofdmgf2to6weeks. Serum fective” in reducing drug abuse but also levels of antidePressant dmg when availthe progmnu negatively affect the availaHydroxyzineisamildamGolytlcwhhsedat~ able may also help to insure that significant bility of needed medici”es fox cherapeuti amounts of drug are being absorbed. Both ing and analgesic popertica that is useful i use. All states should follow the lead of painanddcpmssion incanccrlxxtientsoftcn the anxious cancer uatient with pain. Thi! Wisconsin and the WHO and the INCB in respond to lower doses (25 to 100 mg) of having health care providas and xv&awry antidepressant than are “sully required in O”ebu”d&mgof~ntemlhyd&xyzbx has analgesic activity approaching 8 mg ol officials work togcthex to tear down legal the Physically healthy (100-500 mg). barrierstoeffective~managementrathR morphiw,andhasadditiveimalgesiceffectr than erecting new, ““necessary when combined with morphine. Benzodi, impedimenti. 0 ‘lbe psychostimulants, dextroam&et&“e a2qhm have not been felt to have specific and methylphe”idate, are most helpful for analgesic -es, althcugb they are po Robert Angamla, ID., is a member of the patients with psychomotor slowing and tent anxiolytics. SOme authors have sug- Warhington, DClowJirm ofHyman, Phelps severely dysphmic mood when a rapid dmg gestcd that they have an anti-analgesic ef- and McNamra, P.C He has served as effect is necessary. In low dose, psychosfeet. R=fly> I%xm”&= shwd that al- I Led Advisor to the Unired hhtions IntertinNla”tssthnlllateappetite,ptumase”se prazolam, a unique benmdiazepine with r&ml Narcotics Control Board and of well-being and relieve feelings of weak- lnild antidepressant properties, was a help Generul Counwl to the White House OJ@X ness and fatigue. llxy am also useful in ful adjuvant analgesic in cancer patients of Drug Abuse Policy.

!: 1’ lr

Worth Repeating, from p. 2 viscllxsion lIhisrepoitdescribesourresultswiththeuse of MP as a” adjuvant to narcotic analgesics in 50 patients with advanced cancer. Two cases (4%) developed S”k psychiahic toxicity that requhed discoatinuation of the drug. Althoqtl mco”Ry was cLlmpk& within 24 hr of disx3&““atio” of the drug, bothreactionswereseverea”ddistressing for the medical staff and relative% These hvocasesandthetwocofd&iumwe repmted in our study of mazi”do1 suggest that~~shculdbeusedwilh extmnlecarei”pati~tithadvanced canca,theabsenceofapychiabicorlogical dii does not rule out the possibility of this type of reaction. No additional cases of severe toxicity occl”redafter24hrofeeatment,sIm”gly suggesting that toxicity to Mp occmx early in the treatment and that late severe toxicity is unlikely. I” the group of 44 patients who received the medication for a” average of “lore than a month, MP was “ely welI t&rated, even though the patient popuhtion was extremely ill. RcsponsetoMPwasdetectcdwithi”24to 48hrafterstarUngthebeatment,mdin somccasca,lheimpove~“twas sPectx”hr. Althoughthemainpwemeasued was somnolence, in most cases a significant improvement in pain anl activlty wasalwreported. I”twoprevio”s,p conholled and blinded trials, wehave found that the addition of amphetamine detivafives to tmcaics can significzmtly improve pi”. I”o”rse&mndbial,wechoseMF because of its shoner half life and repotted “se in elderly populatio”s, and used a lower dosethaninourprevio~lstudy. I” this uial, a significant analgesic effect WBS maintained and there was a significat* deCRZEi”dIOwsinesSandi”creaSehlactiV-

ity; toxicity to MP was not significantly different tium toxicity to placebo. The results of this series of Patients suggest that significant tolerance deveQs to MP ovcrapaiodof 1 “lonthoftreahnent. simihu msuks have been suggested by a” uncontm11cdstudyusingdextmamPhetam&. A” alternative expla”ation for the dose bxmase is that higher doses of MP were nexsaty to combat incrwsinp sedation conseque”t to higher opioid doses. The 50 patients lreated with MP mpmsent

a selected popllation receiving oral narcoticsinmodemtelyhighdosesand&eof most of the risk factors for amphetamine. h3ostofthesepatie”tshaverysigGfica”t bnProvement in their quality of life after the addition of hlP to their narcotic repime. Fiiy, it is impntant to recognize the prew”c.7 of organic brain syndromes in a large percentage of Patients with tern&r4 cancer. It is “ecesay to clinically distinguish between the presence of sedation with normal cognitive function and the ~msence ofscdatio”aspanofa”orga”lcbrai”sy”drunle. In the latter group, the addition of an@etxninesislikelytorcs”ltinincrea& confusion and agitatio”. These preliminary results suggest that hlP can be very useful in carefully seleaed groups of patients with pain fmmadva”ced cancer. More research in these areas is badly needed. 0

Vol. 4 No. 3 September 1989

Oral Morphine for Cancer Pain

Number

0

of

133

patients

I

I

I

I

I

I

I

20

40

60

80

100

120

140

Number Fig. 2. Mean

dose of oral morphine

during

of

days

140 days follow-up.

40

30

20

10

I

0

20

I

40

60

80

Fig. 3. Percentage

of patients

120

140

Number of days

Figure 3 0 m m m

100

Vomiting Nausea Constipation Itching with side effects

during

oral morphine

therapy.

134

Vijayaram et al.

scale. In the 19 patients who were lost to followup, the average pain relief was 79%. It is therefore reasonable to conclude that the inability to follow these patients was not related to drug failure. Rather, socioeconomic factors perhaps best explain the difficulty in monitoring patients long-term. The short survival in our population is probably due to advanced disease and the poor nutritional status of our patients. Among those treated with morphine, side effects like nausea and vomiting had a low incidence. Other common side effects of morphine, including constipation, generalized pruritis, and drowsiness, occurred in a few patients at the beginning of treatment. Constipation was not a severe problem, probably because of the usually high ingestion of fiber in the Indian diet. Oral administration of morphine could be maintained in the majority of patients until death. Few required parenteral infusion or injections of morphine. Our experience, which represents the first time that oral morphine therapy has been systematically used in India for the relief of cancer pain, suggests that this approach is one of the most economical and efficient methods available. Oral morphine therapy offers effective and sustained pain control with minimal side effects in the majority of patients.

References 1. WHO Cancer pain relief program. Network News 1986:l.

Journal

of Pain and Symptom Management

2. Twycross RG, Lack SA. Symptom control in far advanced cancer: Pain relief. London: Pitmann, 1983. 3. Saunders CM. The management ness. London: Arnold, 1967. 4. Mount Bromptom malignant 124.

of terminal

ill-

BM, Ajemian J, Scott FJ. Use of the mixture in treating the chronic pain of disease. Can Med Assoc J 1976; 115: 122-

5. Hanks GW, Rose NM, Aherne GW, et al. Analgesic effects of morphine tablets. Lancet 1981; 1:732733. 6. Walsh TD, Saunders GM. Oral morphine for relief of cancer pain. N Engl J Med 1981;305:1417-1418. 7. Foley KM. The treatment Med 1985;313:84-95.

of cancer pain. N Eng J

8. Ventafridda V, Tamburini M, De Conno F. Comprehensive treatment of cancer pain. In: Fields HT, Dubner R, Cervere F, eds. Advances in pain research and therapy. New York: Raven Press, 1985;9:617628. 9. World Health Organization. Cancer Pain Relief. Geneva, World Health Organization, 1986. 10. Arner

S, Arner

B. Differential

effect of epidural

morphine in the treatment of cancer-related pain. Acta Anaesth Stand 1986;29:32-36. 11. Ventafridda V, Oliveri E, Caraceni A, Spoldi E, De Conno F, Saita, and Ripamonti C. A retrospective study on the use of oral morphine in cancer pain. J Pain Symptom Manage 1987;2:77-81. 12. Kaiko PY, Houde of variation Foley KM, search and 13-23.

RF, Wallenstein SL, Rogers AG, Grabinski RW. Clinical analgesic studies and sources in analgesic responses to morphine. In: Inturrisi CE, eds. Advances in pain retherapy. New York: Raven Press, 1986;8: