Epidural versus intrathecal morphine-bupivacaine: Assessment of consecutive treatments in advanced cancer pain

Arid, Epidural versus Intrathecal MorphineBupivacaine: Assessment of Consecutive Treatments in Advanced Cancer Pain Petre Nite~cu, MD, Lennart Appelgren, MD, Lant-grik Linder, MD, Magnus Sj0berg, MD. Erik HeRman, MD, and loan Cure]am, MD

Tn~w ~ ~ multifoa~a~l m u i t ~ (soma~, ~ , and .'~u.~g,rnic) a ~ amcer tmm u,~ ~ sewn~t~rn dmp~ ~u~n~ural(EO)m o r ~ mtd l~vamme u~'eemve,Ud to imtn,,t~n~¢lT) ~ a ~ ~pvaw,~n~. 7"~

IltelTemtmm~t~vtJ~red~otl~mdoj'~ £Dltm,iod. W ~ J i n a l E D ~ s t ~ s i n i t ~ (2~d Ar~)lT deus ~'n muss~, Vae~J~ ~ dme,eV.m~ 7.JJo~ ~o~ ol~e montA of ttselT tnmmm~t, sluiOmgamd u~J~ing scon~ impro~ compar,nt to EO ~ . ~us, t~ IT t n a ~ , ~ ga~ mor~s~isfaao,T pa~n ~el~I,a n ~ - - ~ e

of

(coe~uous mfmionfrom extmml ~ m ~ ) than the El) trm,'tw~. J Pain Symptom

Manage 1990;5:18-26.

r~w~ order, p~n, tpi~u~, ~ A m g , ,~,~urs, n~sAine, ~ p i ~ a i ~

lntrodu~o~ There have been no controlled studies in Patients with intr~table cancer Pain comparinil mp,~t rqNmt, ~ Lemmn AppeliP~n MD. PhD, I ~ n t of A m e m h ~ , Uni~csity of Ged~tbaru, Sahllp~n's Hmpb~|. S.41S45 G~henbarS, Sweden. @U.S.CareerPainRelidCe~aiaee. 1990 l~blitbedby ~ - . r , NewYork,NewYork

the epiduml (ED) and intrathecal (IT} mutes for morphine adminisn'ation in terms of dosage and analgesic efflciency.' When used for postoperative pain relief, the IT mute appeare~ superior to the ED route,i the equianalgesic dose ratio be/nll I0:I? However, it is not presently known whether the equianalgesic ratio estimated for El) and IT administration La acute pintoperative pain can be ~ttapa]ated to career 0Q8~-$924~0#~.50

pain, or if it is constant during the chronic treatment. 4 Regarding this topic, r'z0ombs and colleagues wrote in 1984: "Comparison~ of the outcomes within the cancer group discl,~l no major differences either clinically or in pain reports between epidural and intrathecal morphine." Further, Shetter and colleagues e reported in 1986: "Both epidural and subarachnoid catheter placement were used in our series, and we were unable to draw any conclnsions regarding the relative efficiency of the 2 methods." Finally, Mliller and colleagues mentioned that " . . . No general agreement has been achieved with regard to preference of the route (epidural-intrathecal)." Thus, it appears that the comparative efficiency of ED and IT routes of morphine administration for relief of terminal cancer pain is still an open question. The aim of this study was to compare the el= ficieocy of consecutive periods of ED and I T pain treatment with morphine and bupivacaine (open, subcutaneously tunneled catheters) in patients with severe, multiforal cancer pain, where epidural administration of morphine and bupivacaine failed to give acceptable pain relief.

Pa6ents, Materials, and Metlmds Patients Twenty-live patients (11 men and 14 women), 21 to 80 yr old (median 59 yr), entered the study. The patients were selected for IT treatment when ED administration of morphine and hupivacaine did not give satisfactory pain relief, ie, visual analogue scale (VAS) scores were >5 to 7 (of 10), the systemic opiates and adjuvants caused intolerable side effects, and other therapeutic procedures (eg, neurolysis or cordotomy) were considered contraindicated, unacceptable to the patient, or ineffective in producing lasting pain relief. The study was performed between December 1985 and May 1988. All the patients were followed until death. Fifteen patients had infradiaphragnmtic, and 10 both infra- and supradiaphragmatic pain, which was classified as: somatic, 1; somatic plus ,;iseeral, I; somatic plus neurogenic, 8; neurogenic plus vi.,ceral, 2; all types, ie somatic plus visceral plus neuroganic, 13. The patients and their relatives were given full information on the intratt~ecal treatment, its risks and possible inconveniences and corn-

plications, before entering the study. Inform=~d consent from all the patients includ~'d in the trial was obtained. Meter~ Both the extradural and subarachnoid spaces were catheterized with Portex nylon catheters 900 mm long, 1.1 mm OD, inserted with Tuohy needles 16 or 17 G. Preservative-free morphine solutions 0.2 to 2.0 mg/mL was given in 11 patients, and morphine with preservatives (sodium pyrosulfite 1.0 mg/mL and sodium EDTA 0.1 mg/mL) 10 mg/mL were administered to the other 14. Bupivacaine (Marcaine, ASTRA) 2.5 to 5.0 mg/mL (original solutions), diluted or not with isotonic saline, was added to ranrphine until concentrations judged to be suitable with respect to the daily dosages and volumes were obtained. Methods lmer6~m of ~ Ca//teten. Both ED catheters (n = 42; 1 to 6 per patient) and IT catheters (n = 31; I to 3 per parien0 were inserted using a midline approach at TI 1-12 (n ~ i ) or between TI2-L5 (n = 24). The IT catheters were inserted 1 to 2 interspaees below or above those used for the ED catheters. The ED catheters were introduced 10 to 19 cm from the skin, advanced cranially, and tunneled subcutaneously in the flank 20 to 40 cm from the imenion site. The IT catheters were introduced 12 to 20 ¢m (median 15 era) from the skin, directed cranially, and tunneled subcumneonsly paravertebrally, over the shoulder, and further par~teroally until the second or third chondrocosul joint, a total of 45 to 70 cm (median 50 cm). The ED catheters were considered correctly located in trouble.free insertions, and when analgesia and/or clinical signs of epidural blorl~de were obtained from morphine or/and bupivacaine given through the catheters. The intrathecal catheters ~*ere considered correctly located after: (1) a trouble-free puncture of the dora mater (after identification of the epidural space with "loss of resistance technique" against -A-) and advancement of the catheters into the ~.~barachnoid space; ~ ) free. flow of cerebrespinal fluid (CSF) (the only possible fluid) from the outer end of the ca,.heter after every step of the tunneling and at ~ e end of the imph,~hation procedure; (3) analgesia obtained from a test dose of morphinc and bupivacaine given via the

cethetom (. = 15); (,t) dtntcal sigm of subarachnoid binck ohiained after injection of 10 to 15 mg tetracaine via the catheters (n = 5); or (b) antecopmtarinr and lateral myelogeaphy with injection of metrizamide (Amipaque) via the catheters(. - 5). P ~ Tnmmm:. F.xtradural peried: The wintiont were adrainiuered as intermittent injections 2 to 6 times par day, for a total of 1,942 treatment days (range per patient: 2 to 174 days; median 50 days), lntrathecal period: The treatment started in all patienm, and continued in !8 of them, with intermittent injections given 1 to 15 times/day (mean = 5; median = 2). The total intermittent treatment was 1,150 ueaument days (range per patient: I to 904 days; median = 45 days). In seven patients, the initial, intermittent adminimcation was followed until termination of the tt~ttment by condnuom infusion of morphine, with or without Impivacaine given from an IVAC-.hS0-pump (. I). Tcavenel lnfusor-80 mL (~ ,- 1), Dartec M$26 plunger driver (. = I), or Phammcin CADD-I~,A pump (** = 4). The duration of continuum infm~tm treatment lasted from 14 to 955 days (median .. 158 days), and totaled 815 treatment days. The combined, intermittent, and condnuom treatmeut ranged from I to $05 days (median - 57 days), totaling !,925 treatment days. Eleven patients were treated at home for 7 m 125 days (median - 46 days; total treatment days = 021). &lnemm~ q" Trmam~ E~m~y. Trentment was alaeued for the I~D period and prospectively for the time of the IT treatment. The comparative ef~cacy of the ED and IT treatments was from the amouot of analgesics given by all mutes required to bdng pain relief to an acceptabie levels Thus, every patient was his or her own control. The touti analgesic effect was considered to be an integral of (I) oral. patenferal, and spinal opiate expressed as miUiwam nmrphine equivaleuts par day, (2) *phud tmpivaudne (millifwtms per day), and ($) number of nonopiate anaignic and sedative drull8 edmini.teted every day. The EI~IT treatment el~cttcy was ettimted front both the total analgesic e J ~ and the function of the patient, determined by dldiy activities and the ~oount and pattern of sleep. The dynamics of the IT treatment e ~ t c y was also estin~ted by calculating

the daily dosages for each day (durra8 the first 7 days), each week (during the next $ wh), and each month (for the remaining of the treatment period). Results were considet~l at the following time: (1) initial ( f E D / I - I T ) : second day after start; (2) highest (H-.WT): point of time where the highest daily dosages were given; and iS) final (F-ED/F-IT): second day before termination. Sl~iR/a. The data were processed with a 519+ StatView (Brain Power Inc.) statistical p_~&Tam.~ L'~u~'ipdve and inferential statistics (inclu~g one factor analysis of variance [ANOVA] for repeated measures were used. The results were tested for significance with F'nher's PLSD test, Scheffe's F test, Student's t test for paired samples, and Wilcoxon's signedrank test; p < 0.05 was accepted as significant.

Rmu/ts De~. With the IT treatment, the to,al (all mutes) opiate consumption and the daily dmes of spinal morphine and bupivacalne decreased significantly (p < 0.00001 to p ~, 0,03) at the beginning of the treatment. Both c¢ ntinued m be signffgantly (p < 0.00001 to ~ < 0.05) reduc,~l for a time (up to I wk for spinal . o f phine and bupivacaine and 6 mo for total opiate), and still practically, hut not significantly, reduced in at least 50~ of the patients at the end of treatment (Figures !-8). The I - I T daily dosages cm'reiated with F-ED morphine daily doages (r = 0.63). umqnu r/" Vo/mm a.d D u g ConancmI/ens. As expected, substantially lower volumes and higher concentrations were needed with the IT tt~-atment. This, and the smalier dosages, facilitated the use of portable pumps and home treatment. Both volumet and concentrations increased with duration of the IT treatment (Figure 4). BD tm'mt/T Tl~emnt ~ m t t , ~ . The IT treatment ptve more satisfactory pain zeliaf, more ot~,n ~l~3rted by the patients as complete ~V/xS 0-9), than the ED treatraent, The F - E D / I - I T daily dose ratios were: (l) Total opiate consnmption: median = 7.5 (range 0.6 to 200), (2) Spinal opiate: median = 4 (range 0.8 to 24),

i,'il

higher than the IT ones at the end of the IT period. Both sleep and walking/daily activities were siguificandy improved (Figure 5), while consumption o f nonopiate analgesics and sedatives was not significantly decreased by the IT tTcnUTtent.

~. tO0

tm~td

-

(nIN

w oLn

°

D/scuss/on mrd

ll![

IP(~lIi

--

Inii!gl

Assesmerd ~f lke ED-IT Treatm~ E~aey. Our methods of assessment of the ED and IT treatments periods have been described earlier. In our hands, the alternative of assessing treatment efficacy by die VAS scoies wss unsucce~ful. The reason was that such an assessment needs patient's cooperation, and not all the patients were capable of such cooperation. When V,~S was applicable, "unsatisfactory" pain relief during the ED period was indicated by VAS > 5 - 7 (of 10), and "acceptable" pain ~ l i e f throughout the IT period by VAS 0-2. However, we have chosen not to Fresem incomplete VAS data, It appears that other authors were confronted with similar di~culties. For example, Bonds wrote. "This method, though simple, is not without difficulties, for example it cannot be used if the patient is confused and some elderly patients, and those of log" intelligence, may not be able to master the technique. As with the verbal scale it is open to the influence of personality, the effects of expectation by the doctor upon the patient's performance and various factors in the immediate surroundings." More

M:~

m u m

i EPIOURAL

OuRAnts¢ (deyt) ~ ~

kt

I

IHE~AL PERIOD

t-~lOe 3?

Fig. I. H(f~mt~and:tolal "dl tomes) dailyopiatecomump. tion. Mi~dbpaa¢l: dail~ dose of spinal morphine. Loeyest pea*q:dailydosesof spinalbupivacaine. and (3) Spinal bupivacaine: median = 4 (range: 0,8 to 27). The ratios for all the variables decreased throughout the IT period. The F - E D median daily doses were still 1.5 to 2 times

~

Fit;, 2. U~er l ~ d : total (black color,

ie, the whole bar; n : upper fi~ms)

and spinal (white color; n = lower fig" u~s) opiate daily d~ases. L e ~ ~nel: spinal hupivacainedailydmages.

TOTALOPIATE(1 dey-e m ~ : ~ O . N ~ I ~ AIU) i SPINALOPIATE(I-T day~ P(F,OSeSl-P(~O~ ., I

!7"!I,! lg:!!

I I I~, i

t "1"

FI

. ÷ll ~÷~nll

till

i tOOt-,born LLF

EPIOURAL

C~m110R (d*ys) - - I

PER~O ~,4

"""" '=" ,,s .-.,,.,,.li A' | 1 llulunn-,.. -~-~ t g 34 6 ql ? E 3 4 :~ 3 4 s o r 8 olo DAY8 I WEEK4 I MONTHB INTRATHECAL FERIO0

i" i"

,

i

m

Fig. $. Dim~butions of daily dmages of total opiates (all mutes) and of spln.~J nmrphine and hepiva~ne expressed at 10/25/,~7f~O percentiles + individual dam oots/d~ the 10th to ~ t h W range (symbols, see upper fight comer) in the epidural (I-ED--inidal; F-ED-final) and intrathecal periods. H ~ ~kmd: total opiate daily dma~.-s. M/d~. pane/,' daily doses of spinal motphine. Lou~# page/: daily doses of ~pinal bupivacair~. Note the skewed diltributiom of the three va~aldes,

k

i

" BBA4PmlmI

D, mlfllAnSI[¢.AL M n l ~

recently, Brazenor Is noted in an investigation of IT treatment that, "At the beginning of this mria. there mm comklemble th~,~ht devoted to the best means of evaluating ate e~cacy ot the annlgesia produced. Consideration was 8ivan to the use of the so.called pain 'scales'

such u throe using the principle of a visual analogue. Early experience soon showed, however. that the best and ultimate test whether the method was working was whether the patlent was still using the system and whether other analgesics were still being taken."

lY~/["

(n)

/

ffOTAL 8PINAL VOLUME~

:t6

Fig. 4, upp,~,em,d.,daily,total(morphine + bupi. vacaine) spinal volumes. Lou~r ~ 1 : final drug concenuadonsin the administer~ soludom. inmmIqnm

o

sometimes be controlled with very high doses. The resistance was believed to be produced by the substantial dural thickening caused by chronic catheterization of the epidural space observed in both expefiment~ Is and clinical14 conditions. Our own group (Sjfiberg and colleagues, in preparation), using Portex nylon IT catheters, has found in nine postmortem examinations formation of a thick fibrin sleeve around the extradural segment of the catheter, and practically no sheath on ivi intrathecal trajectory. Confronted with similar clinical situations, Arn~r and Arn~ Is suggested that the IT

Dosages. According to a recent study," approximately 40% of the patients had ED marphina treatment interrupted because of inefficiency, with return to oral administration of the opiate. In that study, median daily doses were higher than in the present investigation: 40 mg (range: 6 to 120 rag) morphine at the start of the treatment, 90 mg (range: 16 to 600 rag) at steady state, and 150 mg (range: 28 to 600 rag) at the final stage. Nath and colleaguesn reported that the neurogenic and visceral pain were usually resistant to ED opiate but could

j

I (nsSS)

Fig. 5. U ~ pared: Sleeppattern scores: 0, canto; 1, <2 hr of uninterrupted sleep;

2, :>2 hr; 3. >4 ht; 4. >6 }.'; 5. 7-8 hr. Zm,~rpud." Wdkin s and daily ~dvity 1~ .

|

tern ~ores: O, bedridden; 1, can be

laLEEP PATTERId

I~=:~l~fn = 0 )

~=eO ~nwl)

IIIHI'Illl a

r

I

2

4

I

~

"

moved; 2, can move independendy, eg. with • wheelchair; S, can walk with

O<&asO# l - l l O.S2

s

-

a

+

a

-

~

cmtchel; 4. can walkwithouthelp;5, returned to am'realactivide~.

I

2 7 DAY8

[

2 4 WEEK8

i

2

~MTRATHEGALP~RIO0

a a MONTHa

a

mute might he advantageous in the treatment of cancer pain restarts to ED morphine. Continuous infusion of ED buplvacaine (480 to 1800 rag/day) in association with ED morphine was a d m i n i ~ by DuPen and l~mnsey.te They reported ED-bupivacaine daily dmages considerably higher than the IT doses used in the present study. Furthermore, even at high dmages of each component, compounding of ED opiate and bupivacaine cannot give acceptable relief of advanced cancer pain in all patients, as it appeared in our study. Our data suggest that the IT administration of opiate and bupivacaine may substantially improve the pain relief at slguificandy lower daily dosages in patients um'esponsive to high ED doses. El) m n m /'/" g ~ mad Drug Ccoummtlies. With the lower opiate and bupivacalne doses, the intrathecal daily volumes were smaller than the ED volumes. However, the IT volumes administered in this study (range: 5 to I14 mL) were substantially larger than those usually used (9,0 to $.0 mL) with some implanted systems, eg, Infasaid (fixed flow rate) pumps.iv Pmsible expianatinns include (i) the intermittent administration used in moot patients; (9) the association of boplvacaine; (5) the use of pumps (eg, IVAC-dS0-POmp and Travenol Infusor) incapable of giving small flow rates, and (4) the unavailahility of higher concentrations of shelf solutions to administer the necessary daily dosages in minimal volumes, Intrathecal daily volumes up to 20 mL/day have no adverse effect (pain at injection, clonus, neurologic deterioration) ,even in patients with the tip of the catheter Incited below a total subarachnoid block, as it was demonstrated in one of our ol~rvations ~Sjdberg and colleagues, in preparation). This mat be explained by the absorption of the cerebrospinal fluid (CSF) from the enclosed subar~chnoid space (below toe block) into the blood via the arachnoid villi (present ainng both the dorsal and ventral roots), or epidural veins, .s or perhaps absorp~ don or the CSF into the lyl~iphatic circulation via the connections of the spinal subarachnoid space with the "segmental" lymphatic venels and nodu, In the latter situation, the points of outflow would be located where digitadom of ligemente dendculata are attached to the dura mater, and the "ink-cuffs" of the nerve roots. TM

Needless m my, insertion of an intratheral catheter is contraindicated in padents with known, high intracranial pressure. However, if the high intracranial pressure is the result of a central nervous system metastasis and occurs after insertion of the catheter, the IT treatment may be continued without further neurologic deterioration, provided that appropriate therapy (diuretics and corticoids) is instituted. &adsfying this condition, we were able to continue the IT treatmem without adverse effects until death (11 m 116 days) in five patients who devehiped high intracranial pressure 11 m 196 days after the start of the IT treatment (Sjdherg and colleagues, unpublished results). The concentrations of IT morphine solutions used in this study (0.25 to 7.5 mg/mL), although significantly higher than those used with the ED treatment, were lower than those (10 m 35 mg/mL) reported with implanted Infusaid pumps.se The concentration of the IT bupivacaine (0.75 m 4.75 mg/mL) were usually above the maximal concentration (0.$7 mg/mL) safely ~sed by Kvoin and colleagues sl in dogs. Our own observations (Sjdberg and colleagues, in preparation) indicate that some painful conditions, e8, pain from the vertebral bodies, or that originating from inmbesacral, brachial, or celiac plexus are unresponsive to IT bupivacaine, even at concentrations of 4.5 to 4.75 mg/mL and high daily clmes and volumes (>100 to 200 mg and >50 mL, respectively). Complete pain relief did not always occur in these conditions, particularly with respect to the pain occurring with body movements and loading, Evidently, even with bopiwcaine administered intrathecally at concentrations of 5 mg/mL, intense nociceptive stimulation can be transmitted to the central nervous system,ss The fear that high concentrations of bupivacaine (eg, 4.5 to 7.0 mg/mL) given intrathecally would cause systemic toxicity seems unjustified. The systemic toxicity of a local anesthetic is more dependent on the dme reaching the systemic circulation per unit of dme than on its concentration in the given solution, Using con. cantrations of 0.5% buplvacaine given extradurelly in daily doses reachinll up to 1,80O m• (approx. 75 mg/hr) for 16 days, DuPen and Ramsey ts were confronted with no signs of systemic toxicity. Giving due consideration m the substantially lower dosages used in our study, one may expect a higher therapeutic ratio for

roi. $ No. l Febnu~1990

Epidumlxe lngraz&r~ Mor~q~eoBu~mine

the IT than for the ED administration of bupivacaine. It appeared from this study that the IT treatment gave more satisfactory pain relief (with lower dosages and volumes) than the ED treatment. The F-ED/ I - I T ratios in our material appeared to be dependent largely on the amount of total and spinal opiate before the I T treatment, association or nonassociation of ED bupivecaine, and on pain location, type, and intensity. When used for postoperative pain relief, the IT morphine appears 10 times more potent than ED morphine." In this study of refractory cancer pain, the mean ratio was approximately 7. In fact, the true ratio could be significandy higher because the pain relief was poor at the end of the ED period (VAS 7-10), and substantially improved, often becoming complete (VAS 0-2) during the IT period. In clinical a/taesthesia, the ED/IT bupivacaine etficacy ratio varies from 2 to 5. and it appeared to be the same irt this study of the refractory cancer pain. The ED/IT ratios decreased throughout the IT period probably more because of progression of ,tisease and changes in pain mechanisms, and less because of changes in receptor seosidvity. 4 The same mechanism might be valid for the spinal bupivaeaine: In some reports, tachyphylaxis did not occur with prolonged--either extcadural2s'~ or intrathecalSl--infusions of bupivacaine, and this finding seemed to be supported by our study in which the median doses of bupivacaine remained practically identical during the whole period of IT treatment. Furthermore. the extent of tachyphylaxis to local aries*liedcs is less if these are g~ven before the pain returns, ~s as it is the case with the c ~tinuous administration of the drugs.

ED versus IT Tl~a,X~tt E ~ t c y .

ED t ~ m s IT "Tlwrapeuti¢ lnd~." The thera-

peutic index of the opiate-bupivacaine infusions, expressed in terms of classical pharmacolok"/, ie, the ratio of the median lethal dose (LDso) to the median effective dose (EDge), is not known in man for obvious reasons. Neither have such investigations been performed in animal experiments. In our clinical experience m date (extended over 100 patients with "refractory" cancer pain), unwanted, adverse effects with intrathecal bupivacaine (unpleasant paresthesias, urinary retention, gait impair-

. 25

ment) occurred in legs than 50% of patients at daily doses of >60 rag, administered as an infu. sion. Further, more than 50% of patients were adequately pain free (VAS 0-2) with daily doses of <30 mg (Sj6berg and colleagues, in preparation)..'Thus, if the therapeutic index is expressed as the ratio of the median dose at which adverse effects occur over the median dose that produces acceptable pain relief, it might roughly be estimated as >2. PraoMca/S~ of t&, Study. IT treatment may improve pain relief in the refractory cancer pain patient when ED opiate and bupivacaine have been proven m be insu~cient. Association of IT bupivacaine probably potentiates the IT morphine, as it does in ED administration, 2e thereby increasing pain relief and maintaining more stable levels of sensory analgesia ~ at lower opiate daily doses, concentrations, and volumes. Adverse effects (unpleasant paresthesia, gait impairment, pareses, orthostatic hypotension) did not occur in patients treated with <60 mg IT--bupivacaine/day given as continuous infusion. Approximately 75% to 95% of patients could be kept acceptably pain-free during fl~, ,*'hole period of treatment with daily doses belo~ that causing adverse effects. I]n some patients, the above-mentioned effects did not occur even at daily doses of 100 to 150 rag/day. Those needing daily dosages >60 rag/day we~ usually bedridden patients, having urinary diversion because of cancer-related complicafio~ (Sj0berg and colleagues, in preparation). Patient's quality of life improved substantially by better pain relief, uninterrupted night sleep, increased appetite, possibility to be treated at home in familiar environment, and higher m,md. We conclude that the IT treatnlent with opiate and bupivacaine may have the following advantages over ED treatment: (1) more satisfactory (often complete) pain relief, (2) more e~cient dosing (lower daily doses and volumes), (3) greater suitability for treatment at home (continuous infusion from external pumps), and (4) better quality of life (sleeping, walking, daily activities).

I. Morgan M. Epidural and intrathecal opioids. Anesth Intern Care 1987;15:60-67.

26

.

.

.

.

Nt~g'a tt aL

~. Ihrmn DW. Suenli J. Pmmperative , r a d i i . in mjor orthopedic ,un~r./. Epidund and intratheol opiates. Anaesthecta 1981;S6:987-941. $. Smdbe~ G. Hednec T. Splmdop~es--pharmacokinetic etcts. In:JB L0~m'6m,U Sjemand. ed~. c o ~ , r e , them ,nd , ~ i n ~ Uochde. ~ m w ~ osy, phylinioSYand clintad etfecu. New York: [bevim'.1988:~9. 4. Am~ S, P.awai N, Gumfmn LL CAinkaiexper;* ence of ImS-tmn tneatmentwith eptdund and intrathecal Opind~--a l~ttionw~desm~ey. Acta Anaesthesin4Scand 1998;$2:25S-259. 5. Coombs WD, Manrer HI.., Saundecs LR, et aL Outcomes and complkatiomof cominuom intr,u~hal macmicanalgesiafor cancer ~ control. J CJin Onml 1984;9:1414-1420, 6. Shetter CA, Hadley NM. Wilkonm~E. Adminisu'ad~n of intmplnal morphine mlfMefor the treat. ment of inuactablecancer pain. Neurmursery 1986; 18:740-747. 7. M011erH, LubenV, ZlmklJ. et al. Lonli4enm,plnd opiate meatmenc Act, Anae,the,io~ Bet8 1988;

~..85-86,

S, Itmtd ItM. Peta--iu ~m~m, a ~ and treatmere. ~ ed. ~dllnber~b, Load~, Melbourne & New York: C~utghillLivinlptone,19~t. 9. Alxtc~ Concep~ Inc, 519*SwtView~. Brain Power, Calabmm, CA 91M~, USA. 10. Bruenor AC~Long.~.m in*mthecaladminiuradon oi"mo~l~hine:A mmpm~m of holm in~..¢ttonvi~ with continuous infu~m by imp~nmt pump. Neurmurllery 1987;21:484-491. II. S j ~ P. Banning MA. Long-term use of epldural opinlds in pad,ram with advancedcancer.Abmacu of the I~hhAnnualMeetinfrof the Scandin,vi. an Almciatkmfor the Studyof Pain, Bemba/Nurmes, Finlsnd, March 20-22.1988:$2. i~, Nath S, Eht'enm6~ S, Retz G, eta], Treatment d a u n t pain with mm'phine--a double blind ,mdy of epidural venus intramuscular mutes of administratinn. Abmam of the 12th Annual Meetingof the Scandinavian Auociatinn for the Study of Pain. Bcymba/Nurmet, Fhdand, Mar~ 20-~2,1988:31. I& Dur~nt CAP, Ysi=h LT. Epidural injectinmof huplvamine, morphine, fentanyl, k~ntenyl, and DADLin chronkany imphmtedtats: A pharmamin~ k~l and p~tholo~ ,tudy. Ane,the,toinsy I ~ ; eq:45-~t3. 14, Coemk. DW, li~tkin JD, Meier F, et aL Neuro. letinm and CSF morphine contemra, tinm dudn 8 chmnk condnuom Intrupt~l m r ,

/ew~d ~¢Paia aad &~Mem. M ~

infusion: A clinical and peatmortem study. pn 1985;22:$$7-$51. • a n ' e 15. Arn~ S, Ara~r B. Differentialeffectsof epidural morphine in the trett~em of cancer related pain. Acta ~ Scand 19~;29:$2-S6. 16. Du Pen IS, Ranaay HD. Compoundinglocalaneghetic* and nan:otk for epldund anatsma in cancer out-lm~nw. Anev,hegolo~ 19~;69:SA. 17. C,oom~ WD. Saundecs LR, GaylorM, ec al. Epidural nucocic infwlon t ~ . q ~ r : implantationtechnklue and elkacy, Aneuhcsioin~ 1982;56:46947& 18. Shanm RT, Evans AJ. The rela6onship of ep~ dural anesthesia to neural memlmmeand mchnoid villi.Anesthesiology1972;$7:545-557. 19. BrierleyBJ, FieldJE. The conney~omof the splnal ,ub4radmoki space with the lymphaticsystem.J Ana¢ 1948;82:198-1645. 20. Yalmh L, Onofrin MB. Retrospective considermion of the dines of morphine siren intrathecallyby chronic infu.b~n in t6s t~tie,!t by t9 phy,lciam. Pain 1987;$1:211-225. ~!. groin SJ, McChmy Jlt, Penn DR, et it. The effeet of chronic mlmradmoid bup~vacaineinfusionin dop. ~ 1987;66:757-742. 22. Lund C, Selmar P, Hammn BO, et aL Effect of Intrathecalbuplvucaineon tometc4ento~evokedpotenthdl folinwtnllderh~toma! stimulation. Anesth Amtlg 1987|66:898-815. 2& h j PP, ~ DD, de Jong ~ . No utchyphylaxis with pmin.g~, continuous bupivacaine, In: Wast HJ, Stanton-Hicks M, eds. New aspects in regional anaettheJia 4. Anaetthesio| Intensive Care Med 1986;176:10-18. 24. Moszmen T, Dtrkec W, BtglecD, et al. No techy. phylaxis during postolzrattve continuous epidural 0,125~ bupivacaiue infusion. R q Anaesth IO.88; i$:117-12L 25. Su~charteGR. Neural physiologyand local anesthecic action. In: Comim MJ, Bridenhaulh PO. eds. Neural blockade in clink~ anesthesia and managemerit of pain, 2nd ed. Philadelphia: Lippincott, 1988:25-45. 98. Akerman B, Arwest~m E, P~t C. Local aneathecics potentiate tphud morphine antinociception. Ane,th Anal8 1998;67:94:~-948. 27. Hjom6 CN, Lend C, MogemenT, et al. gptdural mmphlne improvespal. relief and maintainstenumdlletht during continuous epJdural bupivacaine after atbdomninaJ snr~ery. As~th Analg 191~;6B:I055- lOS6.