The Safety of Concurrent Administration of Opioids via Epiduraland Intravenous Routes for Post-operative Pain in PediatricOncology Patients

Doralina L. Anghelescu, MD, Catherine E. Ross, BA, Linda L. Oakes, RN, MSN, CCNS C, andLaura L. Burgoyne, BM, BSDivision of Anesthesia and Pain Management Service, Division of Patient Care Services, St. JudeChildren’s Research Hospital, Memphis, Tennessee, USA

AbstractSupplementation of epidural opioid analgesia with intravenous opioids is usually avoided becauseof concern about respiratory depression. However, the choice of adjunct analgesic agents for pediatriconcology patients is limited. Antipyretic drugs may mask fever in neutropenic patients, and non-steroidal anti-inflammatory agents may exert anti-platelet effects and interact with chemotherapeuticagents. We examined the safety of concurrent use of epidural and intravenous opioids in a consecutiveseries of 117 epidural infusions in pediatric patients and compared our findings to those reported byother investigators. We observed a 0.85% rate of clinically significant respiratory complications. Thesingle adverse event was associated with an error in dosage. In our experience, the supplementationof epidural opioid analgesia with intravenous opioids has been a safe method of postoperative paincontrol for pediatric patients with cancer.

KeywordsEpidural opioids; postoperative pain; patient; controlled analgesia; respiratory depression; pediatriconcology; cancer

IntroductionThe combination of opioids and local anesthetics has become the standard of care for epiduralanalgesia, because its analgesic effects are greater, and its adverse effects are less, than thoseof local anesthetics alone (1). However, administration of epidural opioids incurs the risk ofrespiratory depression and sedation. Epidural analgesia is typically supplemented with non-opioid analgesic agents such as acetaminophen and non-steroidal anti-inflammatory drugs;intravenous opioids are usually avoided because of early reports of an increased incidence ofrespiratory depression (2).

The choice of adjunct analgesic agents for pediatric cancer patients is limited. Antipyreticagents may mask fever in neutropenic patients, and non-steroidal anti-inflammatory drugs canexert an anti-platelet effect and interact with chemotherapeutic agents (3). Consequently,

Address correspondence to: Doralina L. Anghelescu, MD, Division of Anesthesia, Mail Stop 130, St. Jude Children’s Research Hospital,332 N. Lauderdale St, Memphis, TN 38105-2794, USA, E-mail: doralina.anghelescu@stjude.org.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain.

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Published in final edited form as:J Pain Symptom Manage. 2008 April ; 35(4): 412–419.

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epidural analgesia is frequently supplemented with intravenous opioids at our institution. Herewe report the safety of this practice in our institution’s recent experience and discuss ourfindings in the context of the available literature.

MethodsPatients

This study was approved by the St. Jude Children’s Research Hospital Institutional ReviewBoard, which waived informed consent. Data had been prospectively collected on all patientsconsecutively treated for postoperative pain by continuous epidural infusion betweenSeptember 2004 and July 2006 as part of a Quality Improvement (QI) project led by the PainManagement Service. We identified all cases in which opioids were administered concurrentlyby epidural and intravenous routes. Patients were excluded from analysis if they were olderthan 18 years or if they received opioids by only one route.

Pain ManagementPostoperative analgesia was provided by continuous epidural infusion of bupivacaine 0.1%–0.125% and fentanyl 2–5 mcg/ml, at an hourly rate calculated to deliver 0.5–1 mcg/kg offentanyl per hour. Orders for supplemental analgesia consisted of nurse administeredintravenous doses of opioid as needed (IV PRN). Dose ranges for supplemental analgesia were0.05–0.1 mg/kg of morphine, 0.5–1 mcg/kg of fentanyl and 0.01–0.02 mg/kg hydromorphoneevery 1–2 hours as needed. If patients had a history of opioid tolerance and difficult-to-controlpain, or if IV PRN analgesia failed to control pain, opioid IV patient-controlled analgesia (IVPCA) was provided. The first-line intravenous opioid was morphine; fentanyl andhydromorphone were used as alternatives. The recommended starting PCA bolus doses were:morphine 0.02 mg/kg, hydromorphone 0.004 mg/kg, and fentanyl 0.5 mcg/kg, with a 15-minutelockout interval. If a background infusion was added, the starting dose per hour was equal tothe bolus dose.

Patients were admitted to the general oncology floor or the intensive care unit depending onthe postoperative status, as decided by the anesthesiologist and the surgeon. The presence ofan epidural catheter did not influence admission to a higher acuity floor.

Vital signs (blood pressure, heart rate, respiratory rate, and temperature) were monitored everyfour hours (every two hours in the intensive care unit). Pain intensity, level of consciousness,and motor function were monitored every four hours while patients were awake, and pulseoximetry was monitored continuously. The patient’s level of consciousness was categorizedas alert, drowsy, confused, asleep, or unarousable. Pulse oximetry values were displayed at thenursing station via a central monitoring system. It is our hospital policy to notify the physicianof oxygen saturations <95%, which may prompt an order for supplemental oxygen. For oxygensaturation <90%, there are standing orders to administer supplemental oxygen by simple facemask at 5 liters/minute.

Data CollectionThe medical records of each patient receiving continuous epidural analgesia were examineddaily, and relevant information was stored in the QI database. These data included the nameand concentration of opioid and local anesthetics, the rate of epidural infusion, and anyadjustments to those parameters. Data collected on supplemental intravenous opioid analgesia(IV PRN or IV PCA) included the drug, dose, and time interval. If the method of opioidadministration (IV PRN vs. IV PCA) changed during the 3 to 4 days of concomitant continuousepidural infusion, we counted each patient in the category in which he was placed initially (asIV PRN or PCA). Each patient’s pain score (median and range) was summarized daily in the

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QI database. Age-appropriate pain scales were used: the numeric pain scale (NPS) for childrenolder than 13 years, the FACES pain scale for those 5–13 years of age, and the FLACCbehavioral scale for those younger than 5 years. Any change in respiratory status, includingdecreased respiratory rate, respiratory amplitude, or pulse oximetry values, was recorded inthe database, as were any neurological changes, such as sedation, confusion, hallucination, orseizure. Corrective interventions were also recorded. We examined any adjustments in theepidural infusion rates or composition of the epidural infusate prompted by changes inrespiratory or neurological status.

Definition of Adverse EventsIf neurological or respiratory changes were noted, we examined each incident to determine itsclinical significance and identify possible contributory factors, such as significant comorbidityor additional sedative drugs (e.g., benzodiazepines and phenothiazines). Clinically significantepisodes of respiratory depression were defined as any occurrence of apnea or requirement foraggressive intervention (naloxone administration or intubation) in addition to discontinuationof opioids. Minor respiratory events were defined as a respiratory rate lower than ten breathsper minute and/or oxygen saturation less than 90% on room air, requiring minimal interventionssuch as stimulation, supplemental oxygen, and adjustment of the epidural infusion rate orsubstitution of PRN opioids for PCA opioids.

ResultsPatients

One hundred and forty oncology patients received postoperative epidural analgesia afterthoracotomy, exploratory laparotomy, and lower-extremity surgery. Twenty patients wereexcluded because of age >18 years and three patients were excluded because they receivedopioids by only one route. Therefore, we examined 117 consecutive cases of postoperativepain management given by continuous epidural opioid infusion and concomitant intravenousopioid infusion. Thirty patients (25.6%) were 1–2 years, 35 patients (30%) were 3–10 years,and 52 patients (44.4%) were 11–18 years of age. The mean age was 8 years (range, 8 monthsto 18 years). The intravenous opioids were administered initially as IV PRN doses in 103 casesand by IV PCA in 14 cases. The patients were categorized on the basis of initial therapy, butten “crossed-over” (nine from IV PRN to IV PCA, and one from IV PCA to IV PRN) duringthe course of the continuous epidural infusion, which is typically three days. In the PCA group,five patients had basal opioid infusions augmented by patient-controlled boost doses, and ninehad patient-controlled doses only. The anatomic level of catheter placement and the types ofsurgical intervention are presented in Table 1. The dermatomal level of the block is notroutinely assessed, and was not reported.

Efficacy of AnalgesiaPain was scored as mild (pain score 0–3), moderate (4–6), and severe (>7) on a 1–10 scale.The distribution of pain scores on postoperative days 1 to 3 is shown in Table 2.

Adverse EventsOne clinically significant respiratory adverse event was recorded (0.85%). A 10-month-oldinfant experienced recurrent apnea and bradycardia after inadvertent administration of 5 mgof morphine rather than the 0.5 mg prescribed, while receiving supplemental oxygen. Thiscomplication resolved with stimulation, supplemental oxygen, and discontinuation of theepidural infusion. Minor respiratory events were observed in two patients, 14 and 17 years ofage, who experienced respiratory rates of 7 and 9 breaths per minute, respectively. Neitherpatient required supplemental oxygen and were managed by substituting IV PRN morphine

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for the IV PCA in the former case and by decreasing the rate of epidural infusion in the latter.Naloxone was not required for any episode of opioid-mediated respiratory depression andneither route of opioid administration had to be discontinued.

Safety AnalysisNo neurological complications were observed. Of the three respiratory complicationsobserved, two (including the drug error described above) occurred in the IV PRN opioid groupand one occurred in the IV PCA group in a patient receiving a basal opioid infusion. Only onerespiratory adverse event was clinically significant, and was noted in the IV PRN opioid group.

We also examined the records of the three patients who received opioids via only one route.Two of these patients experienced adverse respiratory events. One patient receiving epiduralfentanyl and bupivacaine after a thoracotomy had arterial oxygen desaturation to 75% whilereceiving supplemental oxygen and had a pleural effusion. The other patient had a respiratoryrate of five breaths per minute while receiving IV PCA opioid and epidural analgesia with localanesthetic only; his lowest oxygen saturation was 94% and he did not receive supplementaloxygen.

Epidural infusion rates were decreased in six cases (6 of 117). Two cases are presented above,and a further four cases did not meet the study criteria for either clinically significant or minorrespiratory events. No adjustments to the concentration of opioid in the epidural infusate wereprompted by respiratory or neurological changes; rather they were prompted by pruritis,hypotension or bradycardia.

DiscussionOnly one of the 117 consecutive pediatric patients who received concomitant epidural andintravenous opioids (0.85%) had a clinically significant respiratory complication, which wasthe result of a drug error. Two other respiratory events were minor and did not result indiscontinuation of the epidural or intravenous opioids.

Continuous epidural analgesia (bupivacaine 0.1%–0.125% and fentanyl 2–5 mcg/ml for 72hours) is the standard postoperative practice at our institution. Although epidural opioidanalgesia is not ordinarily supplemented with IV opioids, it is used for our pediatric oncologypatients for several reasons. First, the choice of agents is limited. Our clinicians are concernedthat acetaminophen may mask fever in neutropenic patients. Nonsteroidal anti-inflammatorydrugs are contraindicated for patients with thrombocytopenia and they interact withchemotherapeutic agents. Second, most of our patients require chronic opioid pain control andhave some degree of opioid tolerance at the time of surgery.

The high rate of supplemental parenteral opioid analgesia in this study is not necessarily areflection of the failure of the epidural analgesia, rather an institutional approach to provideliberal “back up “ analgesia plans for all patients receiving regional or neuraxial analgesia. Thefirst line intravenous opioid supplementation in our practice is PRN administration of IV opioiddoses. The rationale for choosing IV PRN doses as the preferred modality is that our low nurseto patient ratio of 1:2 allows frequent clinical observation and prompt provision of PRN opioidsas necessary. The PRN doses of opioids are ordered with a range of doses, the higher dosebeing one that would be administered in the absence of epidural opioids as a “full dose” andthe lower dose being a “half dose.” The nurses frequently choose the lower dose first, and thenescalate the dose as necessary. IV PCA is used for selected patients with a history of opioidtolerance and pain that is difficult to manage. IV PCA opioids can also be a contingency strategyfor patients whose pain is not adequately controlled by intermittent IV doses. However, becauseone of our 14 patients receiving IV PCA with a basal infusion experienced a minor respiratory

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complication, basal infusion is no longer used in conjunction with IV PCA and epidural opioids,as it may carry a risk of complications. Patients were not randomized to either IV PRN or IVPCA groups, and crossover occurred between the two groups. For both of these reasons noconclusion can be drawn regarding the safety of one rescue technique over the other.

Data about epidural opioid-induced respiratory depression in children are limited. Overall, thereported incidence of respiratory depression associated with epidural opioids is 0% to 1.9% inadults (Table 3) (1,2,4–19) and 0–25% in children (Table 4) (20–30). The rates most commonlyreported in children are 0.5%–1% (24).

The lack of consistent reporting criteria limits the meaningful comparison of studies aboutneuraxial opioids. Some investigators report respiratory depression on the basis of requirementfor naloxone reversal (2,9,11,31), indicating a relatively severe complication. When thisdefinitive criterion is used, the reported rate of respiratory depression with epidural opioids is0.2–0.4% (2,9,11). However, when reduced respiratory rate and oxygen saturation are includedas criteria, rates of 0.07 %–1.2% are reported in adults (Table 3) (4–6,8,11–14,16). Similarly,pediatric studies of epidural analgesia have used two broad definitions of respiratorydepression: 1) clinically significant episodes such as re-intubation, use of naloxone or apnea(20,22,29,30); and 2) definitions that include minor events such as respiratory rate <10 perminute or oxygen saturation < 90% (23,25). One potential criticism of our study is that it didnot use age specific respiratory rates, which may be relevant in small children and babies. Ourdefinitions of adverse respiratory events were designed to be as inclusive as possible, whilstmaintaining comparability to other studies.

The respiratory depression rates associated with epidural and intravenous opioids have beencompared. While morphine administered epidurally appeared to be associated with a lowerrate of respiratory depression (0.4%–0.6%) than IV PCA morphine (1.2%–1.9%) (5,12), asystematic review of randomized controlled studies found comparable cumulative respiratorydepression rates of 1.9% for epidural opioids and 1.8% for IV PCA (19).

In the case of PCA opioid administration in adults respiratory depression rates of 1.2% to 11.5%have been found with meta-analysis and 1.8 % in a systematic review of randomized controlledtrials. In children the incidence of respiratory depression associated with the use of PCA opioidsis 0%–7% (32–35) and at our institution 0.56% (32).

The respiratory depression rate (0.85%) found in our investigation of dual-route opioids iscomparable to that reported for single-route epidural opioid administration or PCA in adultsand children. It is also comparable to our institutional complication rate of 0.56% with PCAopioids alone (32). This result indicates an acceptable level of safety. However, weacknowledge that a second route of opioid administration introduces an additional venue forerror. The only clinically significant respiratory event in our study was caused by a drugoverdose due to human error.

One investigator has reported routine concurrent administration of IV and epidural opioids inadult oncology patients (4). Intravenous morphine given concurrently with epidurally infusedbupivacaine and morphine for postoperative pain was associated with a 0.07% rate ofrespiratory depression requiring reversal with naloxone. This low incidence of respiratorycomplications, as in our patient population, may reflect the increased likelihood of opioidtolerance caused by opioid administration for chronic cancer pain (36).

There are few reported studies of concurrent opioid administration via two routes in non-oncology patient populations. A pediatric study comparing continuous epidural infusion offentanyl and bupivacaine versus intermittent epidural morphine for postoperative pain control

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found no episodes of respiratory depression, despite the concomitant use of IV opioids in 7%and 40% of cases, respectively (27).

In a landmark study, Gustafsson et al. identified concomitant use of intravenous opioids orsedatives, residual anesthesia, supine position, and thoracic level of the epidural infusion asrisk factors for respiratory depression with epidural opioids (2). Other investigators establisheda direct correlation between intraoperative IV fentanyl and postoperative respiratorydepression when epidural opioids were given postoperatively (12).

Our observation of respiratory complications in two of the three patients who received opioidsvia only one route (epidurally or intravenously) suggests that patients’ overall medicalcondition, comorbid conditions, and other individual factors may contribute more significantlyto the risk of respiratory complications than the concurrent administration of opioids byepidural and intravenous routes.

It has been often recommended that sedative-hypnotic drugs not be used together with neuraxialopioids as it may increase the risk of respiratory depression. Two minor respiratory events inour series were in cases in which systemic opioids were combined with additional CNSdepressant medications (an antihistaminic and a benzodiazepine, respectively). However, toplace this in context, the use of benzodiazepines and sedative antihistamines in our institutionis almost universal.

We believe that the opioid tolerance of our patients increases the margin of safety of dual-routeopioids and that our results cannot necessarily be extrapolated to a more general, opioid-naïvepatient population. Moreover, our patients and their families tend to be medically sophisticatedbecause of their prolonged hospital stays and cancer treatment and may be more alert to subtlechanges. Other institutional factors may increase the safety of dual-route opioid administration.Our nurse-to-patient ratio for patients with epidural catheters rarely exceeds one to two, andall nurses complete an epidural competency program that emphasizes the need for carefulmonitoring. Further, patients are monitored continuously by pulse oximetry which is connectedto a central monitoring system with alarms at the nursing station. These advantages may notbe available in all institutions.

Our data suggest that in an appropriate environment it is safe to use intravenous opioids, giveneither PRN or via PCA, to supplement postoperative opioid-containing epidural anesthesia inpediatric oncology patients.

Acknowledgements

We thank Sharon Naron for editorial advice and Poorna Gajjar, RN, for assistance with data collection.

This work was supported in part by U.S. Public Health Service grant CA21765, NIH grant 5 R25 CA23944, and bythe American Lebanese Syrian Associated Charities (ALSAC).

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Table 1Type of Surgery and Location of Epidural Catheter

Level of catheter placement (n) Type of surgeryThoracotomy Exploratory laparotomy Lower extremity surgery

Thoracic (32) 18 14 0Lumbar (84) 6 32 46Caudal (1) 0 1 0Total (117) 24 47 46

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Anghelescu et al. Page 10Ta

ble

2D

istri

butio

n of

Pai

n Sc

ores

on

Post

oper

ativ

e D

ays 0

to 4

Max

imum

Pai

n Sc

ores

Med

ian

Pain

Sco

res

0 to

34

to 6

7 to

10

0 to

34

to 6

7 to

10

Day

0 (n

= 1

01)

42 (4

1.6%

)34

(33.

7%)

25 (2

4.7%

)69

(68.

3%)

22 (2

1.8%

)10

(9.9

%)

Day

1 (n

= 1

08)

46 (4

2.6%

)39

( 36

.1%

)23

(21.

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83 (7

6.9%

)15

(13.

9%)

10 (9

.2%

)D

ay 2

(n =

104

)59

(56.

7%)

26 (2

5%)

19 (1

8.3%

)85

(81.

7%)

14 (1

3.5%

)5

(4.8

%)

Day

3 (n

= 6

7)43

(64.

1%)

17 (2

5.4%

)7

(10.

5%)

55 (8

2.1%

)10

(14.

9%)

2 (3

%)

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Table 3Incidence of Respiratory Depression with Epidural Analgesia – Adult Data

Study, Year, Ref #(n) Study Design Epidural Opioid Incidence ofRespiratoryDepression

Criteria

Wheatley, 2001(1) (1014 –> 1.3 million)

Review of RCTs various 0.24–1.6% Various

Wheeler, 2002(19) (1596) Review of RCTs various E: 1.9%IV PCA: 1.8%IV/IM: 2.4%

Various

Fischer, 1988 (37) (107) Prospective morphine fentanyl 0% “Clinically evident”Ready, 1991(9) (1106) Prospective morphine 0.2% Naloxone useStuart-Taylor, 1992(13)(800)

Prospective diamorphine 0.9% RR < 10/min

de Leon-Casasola, 1994a(4) (4227)

Prospective morphine 0.07% RR < 10/min prompted use ofnaloxone per protocol.

Scott, 1995(11)(1014) Prospective fentanyl RR<8/min: 1.2%,Naloxone: 0.4%

RR < 8 Naloxone use

Rygnestad, 1997 (10)(2000)

Prospective morphine Overall: 1.6%Severe: 0.15%

Considered severe if infusionwas stopped.

Liu, 1998b (8)(1030) Prospective fentanyl 0.3% RR < 8/minFlisberg, 2003(5) (2696) Prospective morphine IV PCA: 1.2%

PCEA: 0.4%RR < 8/min

Shapiro, 2005(12) (1524) Prospective morphine Overall: 1.2%IV PCA: 1.9%E: 0.6%IT: 0.7%

RR < 10/min

Burstal, 1998(38) (1062) Prospective survey various 0.32% RR < 8 and sedationFuller, 1990(6) (4880) Retrospective morphine 0.25% RR < 10/minTsui, 1997(14) (1466) Retrospective morphine fentanyl IV PCA: 1.97%

E: 0.6%RR < 10/minSpO2 < 90%PCO2 > 7kPa

Wigfull, 2001b (16)(1057)

Retrospective fentanyl 0.19% RR < 8/min

RCT = randomized controlled trial; E = epidural; IV = intravenous; PCA = patient controlled analgesia; IM = intramuscular; RR = respiratory rate; PCEA= patient controlled epidural analgesia; IT = intrathecal; SpO2 = arterial oxygen saturation; pCO2 = arterial carbon dioxide partial pressure.

aUsed intravenous morphine as supplementary analgesia.

bUsed patient-controlled epidural analgesia.

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Anghelescu et al. Page 12

Table 4Incidence of Respiratory Depression with Epidural Analgesia – Pediatric Data

Study, Year,Ref #(n)

Study Design Opioid Incidence ofRespiratoryDepression

Criteria

Krane, 1989(26)(32)

RCT morphine 3.1% Not specified

Kart, 1997a(31) RCT fentanyl morphine 0% Not specifiedGoodarzi, 1999(23) (90)

RCT morphine fentanyl hydro-morphone

morphine: 25%(none severe)fentanyl: 0%hydromorphone:0%

RR < 10/min, SpO2 < 90%

Attia, 1986(20)(20)

Prospective morphine 0% Apnea

Krane, 1987(25)(46)

Prospective morphine 0% RR<10/min

Lovstad, 1997(28) (100)

Prospective fentanyl 0% Treatment with rescuemedication

Giaufre, 1996b(22) (15,013)

Prospective survey various 0.006% Apnea

Shayevitz, 1996(30) (54)

Retrospective case control morphine E: 0%IV: 0%

Delayed extubation,reintubation, naloxone use

Valley, 1991(29) (138)

Retrospective morphine 8% Apnea, desaturation,bradycardia, decreasedRR, treated withstimulation, intubation, ornalaxone

Flandin- Blety,1995(21) (7200)

Retrospective questionnaire various 0% Various, not specified

Williams, 2003(24)

Retrospective questionnaire various Overall: 0.1–5% Various, not specified

RCT = randomized controlled trial; IV = intravenous; RR = respiratory rate; SpO2 = arterial oxygen saturation; E = epidural.

aUsed intravenous morphine as supplementary analgesic.

bUsed mostly caudal blocks.

AU: PLS CHECK SUPERSCRIPTS AS THEY HAD TO BE CHANGED TO CONFORM TO JOURNAL STYLE. ALSO, IS THE ADDITION OF REF# TO COLUMN 1 OKAY WITH YOU?

J Pain Symptom Manage. Author manuscript; available in PMC 2009 April 1.