Postoperative Analgesic

m REVIEW ARTICLE

Dennis M. Fisher, M.D., Editor

Anesthesiology1999; 91:191927 1999 American Society of Anesthesiologists, Inc.Lippincott Williams & Wilkins, Inc.

Intraoperative and Postoperative Analgesic Efficacyand Adverse Effects of Intrathecal Opioids in PatientsUndergoing Cesarean Section with Spinal Anesthesia

A Qualitative and Quantitative Systematic Review of RandomizedControlled TrialsJrgen B. Dahl, M.D., Ph.D.,* Inge S. Jeppesen, M.D., Henrik Jrgensen, M.D., Jrn Wetterslev, M.D., Ph.D.,*Steen Miniche, M.D.

SPINAL anesthesia is commonly used for cesarean sec-tion, and it has become a popular practice to add opioidsto spinal solutions to enhance and prolong intraopera-tive and postoperative analgesia. Morphine and fentanylare the opioids most often used for this purpose, butthere is not a general consensus about the benefits of thevarious regimens, and the incidence of side effects withdifferent opioids and doses is controversial.

Recently, a number of systematic reviews have beenpublished in the field of pain and perioperative medi-cine.13 The aim of a systematic review is to summarizeavailable information from controlled clinical trials toproduce evidence-based estimates of the true clinicaleffect of an intervention.46 The purpose of this system-

atic review was to investigate the effect of intrathecalopioids added to spinal anesthesia on intraoperative andpostoperative pain and to evaluate adverse effects inpatients scheduled for cesarean section, using evidencefrom all relevant randomized controlled and blindedtrials.

Methods

Systematic Search and Validity ScoreReports of randomized controlled trials of opioid

added to spinal anesthesia in patients undergoing cesar-ean section were sought systematically. Only reportsthat examined a single dose of opioid added to a spinalanesthetic and that included a postoperative pain out-come were considered. Only reports that compared opi-oid against placebo (e.g., saline) or no treatment wereincluded in the analysis.

Reports were identified using The Cochrane Library(1998, issue 2) and the MEDLINE (19661998) andEMBASE (19811998) databases without language re-striction. We used different search strategies with free-text combinations, including the following key words:spinal, subarachnoidal, intrathecal, opioid, anesthesia,local anesthesia, postoperative analgesia, and cesareansection (date of final search: July 15, 1998). Referencelists of retrieved reports and review articles weresearched systematically. No abstracts or unpublished ob-servations were included. Authors were not contactedfor original data.

* Consultant, Department of Anesthesiology, Herlev University Hos-pital.

Consultant, Department of Anesthesiology, Glostrup UniversityHospital, Glostrup, Denmark.

Research Fellow, Department of Anesthesiology, Herlev UniversityHospital.

Registrar, Department of Anesthesiology, Herlev University Hospi-tal.

Received from the Department of Anaesthesiology, Herlev Univer-sity Hospital, Herlev, Denmark. Submitted for publication August 27,1998. Accepted for publication June 28, 1999. Support was providedsolely from institutional and/or departmental sources.

Address reprint requests to Dr. Dahl: Department of Anaesthesiol-ogy, Herlev University Hospital, DK-2730 Herlev, Denmark. Addresselectronic mail to: [email protected]

Key words: Metaanalysis; opiates; side effects; subarachnoidal.

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Anesthesiology, V 91, No 6, Dec 1999

Table 1. Summary of Randomized Controlled Studies of the Postoperative Analgesic Effects of Intrathecal Opioids in Caesarean Section

ReferenceQualityScore

Number ofPatients

Treatment/Control

LocalAnesthetic Opioid

PostoperativePain ScoreCompared

with Control

PostoperativeSupplemental Analgesic

Consumption/orNumber of Patients

Needing SupplementalAnalgesics Compared

with Control

Time to FirstPostoperative

AnalgesicCompared with

Control Comments

9 2 11/10/12 Bupivacaine,9.7511.25mg,hyperbar

Morphine0.1 mg0.25 mg

P , 0.05P , 0.05

Pain scores reduced 324 h postop

10 3 17/17 Bupivacaine,9.3 6 0.2mg,hyperbar(mean 6SEM)

Morphine0.2 mg P , 0.05 P , 0.05

Number of patients needing supplanalgesics 024 h postop: 6:17vs. 17:17 in active vs. controlgroupSuppl morphine consumption 024 h postop (mg): 7.2 6 3.9 vs.26.8 6 5.6 in active vs. controlgroup (mean 6 SEM)

11 4 29/21 Bupivacaine,9.3 6 0.02mg,hyperbar1 0.2 mgadr (mean6 SE)

Morphine0.2 mg P , 0.05 P , 0.05

Number of patients needing supplanalgesics 024 h postop: 14:29vs. 21:21 in active vs. controlgroupSuppl morphine consumption 024 h postop (mg): 11.1 6 1.3 vs.22.2 6 2.5 in active vs. controlgroup (mean 6 SEM)

12 2 20/20/20/20 Tetracaine,10 mg,hyperbar

Morphine0.05 mg0.1 mg0.2 mg

P , 0.05P , 0.05P , 0.05

NSP , 0.05P , 0.05

Suppl analgesic consumptionevaluated 024 h postop(indomethacin)

13 4 30/30 Bupivacaine,1314 mg,hyperbar

Morphine0.1 mg P , 0.05 P , 0.05

Pain (VAS) reduced 4 and 24 hpostopSuppl morphine consumption 024 h postop (mg): 10 (432) vs.29 (1632) in active vs. controlgroup (median, interquartilerange)


Morphine0.1 mg P , 0.05 P , 0.05 P , 0.05

Pain (VAS) assessed from 124 hpostopSuppl analgesic consumptionevaluated 024 h postop(keterolac)

15 3 6/8/7/7/6/7/5/9 Bupivacaine,0.75%,hyperbar

Fentanyl2.5 mg

5 mg6.25 mg12.5 mg25 mg37.5 mg50 mg

NSNSNSNSNSNSNS

NSNS

P , 0.05P , 0.05P , 0.05P , 0.05P , 0.05

16 3 12/12 Bupivacaine,12.5 mg,hyperbar

Fentanyl10 mg P , 0.05

17 2 30/30/30/30 Bupivacaine,15 mg,hyperbar

Fentanyl20 mg40 mg60 mg

NSP , 0.05P , 0.05

P , 0.05P , 0.05P , 0.05

Suppl analgesic consumption 024h postop: 2.4 6 0.6 vs. 1.6 6 0.6vs. 1.2 6 0.5 vs. 2.7 6 0.7 mg/kgof fentanyl in group 20, 40, 60 mgand control, respectively (mean6 SD)

18 3 14/14 Lidocaine, 80mg,hyperbar

Fentanyl15 mg NS P , 0.05


Fentanyl25 mg NS NS NS


Fentanyl10 mg NS NS

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DAHL ET AL.


Each report that met the inclusion criteria was readindependently by three of the authors and scored usinga three-item, 15-score quality scale.5 Consensus wassubsequently achieved. If the reports were described asrandomized, one point was given, and an additionalpoint was given if the method of randomization wasdescribed and considered adequate (computer-generat-ed, table of random numbers, etc.); however, one pointwas deducted if randomization was inappropriate (alter-nate randomization, randomization according to week-day, etc.). If trials were described as double-blind, onepoint was given. An additional point was given if blind-ing was described and considered appropriate (blindedpharmacy-manufactured ampules, etc.), but one pointwas deducted if blinding was inappropriate. Finally, re-ports that described the numbers and reasons for with-drawals were given one point. By definition, studieswithout randomization and blinding were excluded.Thus, the minimum score of an included randomizedcontrolled trial was 2 and the maximum score was 5.

Data Extraction and AnalysisInformation about patients, type and dose of local

anesthetic, and opioid used for spinal anesthesia andanalgesia, study end points, adverse effects, and obser-vation periods were taken from each report.

When possible, retrieved data were analyzed quantita-tively. We used a metaanalysis to calculate the weightednumber needed to treat (NNT) or number needed toharm (NNH) with 95% confidence intervals (CIs), count-ing the dichotomous outcome for all the individualsacross all included studies, i.e., a fixed-effects model.NNT refers to the number of patients needed to treat toyield one successful outcome. NNH refers to the numberof patients needed to treat to harm one individual.4,7,8 Asignificant difference between NNT or NNH was as-sumed when CIs did not overlap. This is a conservativecriterion because it involves the comparison of an im-probable extreme for one estimate with an equally im-probable extreme for the other.2 When one bound of theCI was `, this indicated that the CI included no benefitor harm of the intrathecal opioid over placebo/control.Data from control patients in studies investigating morethan one opioid or dose (more than one treatment arm)were included in more than one analysis, but controldata were not counted more than once for the combinedanalysis. NNT was calculated for number of patients notneeding supplemental intraoperative analgesics.

Data on postoperative pain scores and supplementalanalgesics were insufficient to perform a quantitativeanalysis and were evaluated qualitatively. In this analysis,effectiveness was defined as a significant difference (as

Table 1. Continued

ReferenceQualityScore

Number ofPatients

Treatment/Control

LocalAnesthetic Opioid

PostoperativePain ScoreCompared

with Control

PostoperativeSupplemental Analgesic

Consumption/orNumber of Patients

Needing SupplementalAnalgesics Compared

with Control

Time to FirstPostoperative

AnalgesicCompared with

Control Comments


Fentanyl10 mg NS


Fentanyl15 mg NS P , 0.05

20 4 20/20/20 Bupivacaine,12.5 mg,hyperbar

Sufentanil2.5 mg5 mg

P , 0.05P , 0.05

P , 0.05P , 0.05

Suppl morphine consumption 06 hpostop (mg): 8 6 9 vs. 6 6 11 vs.19 6 12 in group 2.5 vs. 5 mgsufentanil vs. control, respectively(mean 6 SD). No difference inopioid consumption from 624 hpostop

22 3 9/9/9/10 Bupivacaine,10.5 mg,hyperbar

Sufentanil10 mg15 mg20 mg

P , 0.05P , 0.05P , 0.05

23 2 15/15/15 Bupivacaine,22.5 mg(hyperbar)

Buprenorphine0.03 mg0.045 mg

P , 0.05P , 0.05

NS 5 no significant difference, as reported in the original study; 5 no data available; suppl 5 supplemental.

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INTRATHECAL OPIOIDS IN CESAREAN SECTION


reported in the original trials) between the active andthe control groups in three different measures of anal-gesic efficacy: postoperative pain intensity (visual analogscore or similar pain scores), time to first administrationof postoperative analgesic, or total consumption of post-operative analgesic.

Four different side effects were extracted in dichoto-mous form (presence or absence of side effect) andevaluated quantitatively with calculation of NNH: pruri-tus, nausea, vomiting, and respiratory depression (de-fined as respiratory rate , 10 breaths/min).

Evidence for a dose response was assumed when CIsbetween NNT or NNH of two doses or dose ranges didnot overlap (see above).2 In addition, the doseresponserelationship between pruritus, nausea and vomiting, andintrathecal morphine, fentanyl, or sufentanil was evalu-ated by means of univariate logistic regression.

Results

Fifteen reports fulfilled the inclusion criteria.923 Inthese reports, 535 patients were given four differentopioids (morphine, fentanyl, sufentanil, buprenorphine)in 32 treatment arms and 23 different doses (table 1);281 patients served as controls. In one study, fentanyldoses were weight normalized.17 For the quantitativeanalysis, these doses were recalculated to total dosebased on the demographic data provided in the report.17

Two studies compared two different opioids.14,20 Threedifferent local anesthetics were used for spinal anesthe-sia: bupivacaine (13 studies), lidocaine (one study), andtetracaine (one study; table 1).

Studies by the following investigators were excludedfrom the final analysis: Pan et al.24 (single-blinded), Chuet al.25 (no information about blinding), and Cooper etal.26 (administration of epidural fentanyl intraoperativelyin a fraction of patients).

Analgesic EfficacyPostoperative Pain Scores. Only four studies with a

total of six treatment arms evaluated postoperative painscores beyond the time to first administration of supple-mental analgesic (table 1).9,13,14,19

Abboud et al.9 reported prolonged postoperative painrelief of $ 50% as measured with visual analog scorewith morphine 0.1 mg and 0.25 mg compared withcontrol. Morphine (0.1 mg) decreased pain scores for24 h postoperatively in two other studies.13,14 Fentanyl(10 mg and 25 mg) had no effect on pain scores during

24 h postoperatively in the studies by Olofsson et al.19

and Sibilla et al.,14 respectively.Time to First Administration of Supplemental An-

algesic Postoperatively. Data on time to first adminis-tration of supplemental analgesic postoperatively couldbe extracted from 12 studies (table 1).1012,1418,2023

The criteria for this outcome was clearly specified in 10studies: time from subarachnoid administration of opioidto patient request for analgesia was the criterion in eightstudies,1012,14,1618,23 and time to visual analog score .3 or 4 was the criterion in two studies.20,22 In two otherstudies,15,21 no distinct criteria could be derived fromthe reports.

The median time to first administration of analgesic withlocal anesthetic alone (control) was 2 h (range, 14 h) in 10studies with bupivacaine, and 1 h and 8 h in two studieswith lidocaine and tetracaine, respectively (fig. 1).

Morphine was evaluated in four studies1012,14 with atotal of six treatment arms and three doses (table 1).Morphine at doses of 0.1 mg and 0.2 mg increased thetime to first administration of analgesic in all five com-parisons, whereas a 0.05-mg dose had no significanteffect on this outcome in one study. In one study, ad-ministration of 0.05 mg, 0.1 mg, and 0.2 mg morphineshowed no clear doseresponse relationship.12 Figure 1shows time to first postoperative analgesic for the differ-ent studies and treatment arms. Median time to firstanalgesic with the various effective doses of morphinewas 27 h (range, 1129 h).

Fentanyl was evaluated in seven studies1418,20,21 witha total of 15 treatment arms and 12 doses (table 1). In thestudy by Hunt et al.,15 seven doses of fentanyl, from 2.5mg to 50 mg, were examined, but only data with 6.25 mgare reported. Except for four comparisons with 2.5 mg,5 mg, 10 mg, and 25 mg fentanyl, respectively,14,15,20 allcomparisons with doses of fentanyl . 6.25 mg increasedtime to first administration of analgesic. In one study,administration of 20 mg, 40 mg, and 60 mg fentanylyielded evidence of a doseresponse relationship.17 Me-dian time to first analgesic with the various effectivedoses of fentanyl was 4 h (range, 213 h; fig. 1).

Finally, two doses of buprenorphine were evaluated inone study,23 and five doses of sufentanil were evaluated intwo studies20,22 (table 1). Both drugs increased time to firstadministration of analgesic with all doses (fig. 1). The in-crease with the various doses of sufentanil showed noevidence of a doseresponse relationship.20,22

Consumption of Postoperative Supplemental An-algesics. Data on consumption of postoperative supple-mental analgesics could be extracted from 11 studies

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DAHL ET AL.


(table 1).1015,1721 Morphine was evaluated in five stud-ies1014 with a total of seven treatment arms and threedoses. Morphine at doses of 0.05 mg, 0.1 mg, and 0.2 mgdecreased consumption of postoperative supplementalanalgesic from 0 to 24 h postoperatively in all compari-sons.1014

Fentanyl was evaluated in six studies14,15,1719,21 with atotal of 14 treatment arms and 12 doses. Except for onestudy in which 40 mg and 60 mg fentanyl decreasedconsumption of supplemental analgesic from 0 to 24 h

postoperatively,17 no effect of intrathecal fentanyl wasdemonstrated on this outcome.

Sufentanil was evaluated in one study.20 Sufentanil atdoses of 2.5 mg and 5 mg decreased consumption ofpostoperative supplemental analgesics from 0 to 6 h butnot from 6 to 24 h postoperatively. No data are availableon buprenorphine.

Number of Patients Not Needing SupplementalAnalgesics Intraoperatively. Data could be extractedfrom 13 studies; 485 patients received opioid, and 254

Fig. 1 Time to first administration (hours)of postoperative supplemental analgesicsin patients receiving spinal anesthesiawith local anesthetic alone (solid bars)or local anesthetic combined with bu-prenorphine, sufentanil, fentanyl, ormorphine in varying doses (variousbars). NS 5 no statistically significant dif-ference from control.

1923



patients served as controls.1021,22 Ten of 28 compari-sons showed significant reduced need for intraoperativeanalgesic with intrathecal opioid over control. Pooledresults from all opioids and doses showed that the num-ber of patients not needing supplemental analgesics in-traoperatively was 464 of 485 (96%) with treatment and192 of 254 (76%) with control. The median NNT for notneeding any supplemental analgesics intraoperativelywas 4.9 (range, 3.96.9), with no significant differencesbetween the various opioids. Combined analysis of datafrom 0.1 mg versus 0.2 mg morphine, and 1535 mgversus 4060 mg fentanyl showed no significant differ-ences between the two doses/dose ranges, i.e., no evi-dence for a doseresponse relationship.

Adverse EffectsPruritus, nausea, vomiting, and respiratory depression

were reported in 11,915,17,20,22,23 11,915,17,2123

8,914,17,23 and 12 studies,915,17,2023 respectively (table2). Observation periods for side effects were 024 hpostoperatively in 9 studies911,1315,17,20,21 and untilfirst narcotic administration,22 012 h,23 and 048 h12

postoperatively in three other studies, respectively. Datafrom all studies, irrespective of observation periods, are

pooled in the quantitative analysis. NNH for the differentadverse effects and opioids is shown in table 2. PooledNNH for all opioids and doses indicated that both pruri-tus and nausea and vomiting occurred significantly moreoften with intrathecal opioids than with control. Whenanalyzed separately, however, only morphine increasedall three adverse effects, whereas fentanyl and sufentanilincreased pruritus, but not nausea and vomiting, com-pared with control. The number of patients needed totreat with 0.050.25 mg morphine to harm one individ-ual was 2.6 (95% CI, 2.13.3) for pruritus, 6.3 (95% CI,4.212.5) for nausea, and 10.1 (95% CI, 5.741.0) forvomiting, respectively. NNH for pruritus with 2.560 mgfentanyl and 2.520 mg sufentanil was 2.2 (95% CI,1.82.7) and 1.4 (95% CI, 1.11.9), respectively, and wasnot significantly different from NNH with morphine (ta-ble 2). Data for buprenorphine and sufentanil are basedon few studies and should be interpreted with caution.Combined analysis of data from 0.1 mg versus 0.2 mgmorphine and 1535 mg versus 4060 mg fentanylshowed no significant differences between doses, ex-cept for pruritus with fentanyl, with an NNH of 3.3 (95%CI, 2.35.4) versus 1.5 (95% CI, 1.31.9) with the low-and high-dose ranges, respectively. A trend toward re-

Table 2. Adverse Effects (Pruritus, Nausea, Vomiting) with Intrathecal Opioids Compared with Control

Event/Opioid

Number ofStudies/

TreatmentArms

Number ofPatients,

Treatment/Control

Response withTreatment (%)

(95% CI)

Response withControl (%)

(95% CI) NNH (95% CI)

PruritusMorphine 0.050.25 mg 6/9 182/126 51 (4459) 12 (719) 2.6 (2.13.3)Fentanyl 2.560 mg 3/11 166/65 49 (4157) 3 (013) 2.2 (1.82.7)Sufentanil 2.520 mg 2/5 67/10 84 (7392) 10 (045) 1.4 (1.11.9)Buprenorphine 0.03

0.045 mg 1/2 30/15 10 (227) 0 (022) 10.0 (4.8`)All drugs and doses 11/27 445/190 52 (4857) 9 (514) 2.3 (2.02.7)

NauseaMorphine 0.050.25 mg 5/8 152/96 21 (1528) 5 (212) 6.3 (4.212.5)Fentanyl 2.560 mg 4/12 186/85 14 (920) 9 (418) 21.9 (8.0`)Sufentanil 2.520 mg 1/3 27/10 33 (1754) 10 (045) 4.3 (2.0`)Buprenorphine 0.03

0.045 mg 1/2 30/15 30 (1549) 7 (032) 4.3 (2.338.0)All drugs and doses 11/25 395/180 19 (1523) 9 (514) 9.7 (6.221.5)

VomitingMorphine 0.050.25 mg 6/9 182/126 19 (1325) 9 (415) 10.1 (5.741.0)Fentanyl 2.560 mg 2/4 119/56 6 (212) 4 (012) 43.3 (11.4`)Sufentanil 2.520 mg Buprenorphine 0.03

0.045 mg 1/2 30/15 23 (1042) 7 (032) 6.0 (2.7`)All drugs and doses 8/15 331/171 15 (1119) 8 (413) 14.5 (8.170.9)

NNH 5 number-needed-to-harm; ` 5 infinity (absence of a statistically significant difference); CI 5 confidence interval. The All drugs and doses number ofstudies may not be equal to the sum of studies with the various opioids because some studies evaluated more than one opioid.

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DAHL ET AL.


duced NNH with higher doses was demonstrated withmost opioids (tables 3 and 4). With univariate logisticregression analysis, the relative risk of postoperativepruritus increased with increasing doses of morphine(P , 0.00001), fentanyl (P , 0.002), and sufentanil (P ,0.002). Likewise, logistic regression analysis showed thatincreasing the dose of morphine increased the relativerisk of postoperative nausea (P , 0.00001) and vomiting(P , 0.006).

Data on respiratory depression were reported in 12studies, with 485 patients receiving opioids and 250patients serving as controls. The criterion for respiratorydepression was respiratory rate , 10 breaths/min in allstudies except two,12,21 with respiratory rate , 8breaths/min. Respiratory depression was only noted inone study13 in which one patient receiving 0.1 mg mor-phine had an episode of respiratory rate , 10 breaths/min. Consequently, pooled NNH for respiratory depres-sion with intrathecal opioids (all opioids and doses) washigh (476; 95%CI, 164`) and not significantly differentfrom control.

Discussion

The main finding of this systematic review was thatintrathecal morphine prolonged time to first postopera-tive analgesic administration and created a clinically rel-evant reduction in postoperative pain, whereas fentanyland sufentanil were not effective to any clinically signif-icant extent.

Only one randomized, placebo-controlled study hasmade direct comparisons between intrathecal morphineand lipid-soluble opioids in patients undergoing cesareansection.14 In this study, the quality of postoperative analge-sia with 25 mg fentanyl was inferior to that with 0.1 mgmorphine and not different from placebo. The incidence ofpruritus, but not nausea and vomiting, was less with fent-anyl compared with morphine.14 It may be difficult tomake useful direct comparisons between single doses ofmorphine and fentanyl in postoperative pain because ofdifferences in pharmacokinetic profiles. Nevertheless, thepresent metaanalysis confirms that 1025 mg fentanyl, asstudied by Sibilla et al.14 and other investigators,15,16,1821

Table 3. Dose-related Adverse Effects (Pruritus, Nausea, Vomiting) with Intrathecal Morphine 0.1 mg and 0.2 mgCompared with Control

Dose,Morphine

Number ofStudies

Number of Patients,Treatment/Control


(95% CI)

Response withControl (%)

(95% CI) NNH (95% CI)

Pruritus0.1 mg 4 85/88 53 (4264) 10 (519) 2.3 (1.83.3)0.2 mg 3 66/58 53 (4065) 9 (319) 2.3 (1.73.3)

Nausea0.1 mg 3 55/58 16 (829) 5 (114) 9.9 (4.4`)0.2 mg 3 66/58 35 (2448) 7 (217) 3.6 (2.46.8)

Vomiting0.1 mg 4 85/88 21 (1331) 9 (417) 8.3 (4.465.4)0.2 mg 3 66/58 20 (1131) 5 (114) 6.9 (3.929.8)

Table 4. Dose-related Adverse Effects (Pruritus, Nausea, Vomiting) with Intrathecal Fentanyl 1535 mg and 4060 mgCompared with Control

Dose,Fentanyl

Number ofStudies

Number of Patients,Treatment/Control


(95% CI)

Response withPlacebo (%)

(95% CI) NNH (95% CI)

Pruritus1535 mg 3 65/65 34 (2347) 3 (011) 3.3 (2.35.4)4060 mg 3 65/39 68 (5579) 3 (013) 1.5 (1.31.9)

Nausea1535 mg 4 85/85 9 (418) 9 (418) `4060 mg 3 65/39 6 (215) 5 (117) 97.5 (9.9`)

Vomiting1535 mg 2 59/56 7 (216) 4 (012) 31.2 (8.9`)4060 mg 2 60/30 5 (114) 3 (017) 60.0 (9.9`)

NNH 5 number-needed-to-harm; ` 5 infinity (absence of a statistically significant difference); CI 5 confidence interval.

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does not provide meaningful postoperative analgesia. How-ever, the analysis does not confirm that intrathecal mor-phine is more likely to cause pruritus than the lipid-solubleopioids. Thus, another finding of our review was that theincidence of pruritus is very high, but similar, with mor-phine, fentanyl, and sufentanil. However, nausea and vom-iting occurred less frequently with the lipophilic opioidsthan with morphine.

It may be speculated whether larger doses of fentanylproduce clinically significant postoperative analgesia.The evidence from the available controlled clinical trialsis controversial. Two studies have investigated dose re-sponse with intrathecal fentanyl on postoperative anal-gesic effectiveness. In one study, no further increase induration of analgesia nor decrease in 24-h opioid require-ments was observed when the dose of intrathecal fent-anyl was increased to . 6.25 mg.15 However, the resultsfrom this study should be interpreted with care becauseeach study group included very few patients (table 1),with a major risk of committing a type II error. Inanother study,17 time to request of postoperative anal-gesic increased and total analgesia consumption de-creased in a dose-dependent manner when intrathecalfentanyl was applied in doses of 20 mg, 40 mg, and 60 mg.Thus, time to first postoperative analgesic request in-creased from 3 h with control to 11 h and 13 h with 40mg and 60 mg fentanyl, respectively. Pruritus, but notnausea and vomiting, increased with increasing doses offentanyl.17 The latter study indicates that 4060 mgfentanyl may indeed produce meaningful postoperativeanalgesia with relatively few adverse effects.

A major end point in a number of the retrieved reportswas the effect of intrathecal opioids on intraoperativeanalgesia.14,16,1821 Our quantitative analysis demon-strated that only 24% (95% CI, 930%) of patients in thecontrol groups required supplemental analgesics intra-operatively. This means that a substantial number ofpatients given intrathecal opioids for intraoperative an-algesia will be exposed to unnecessary adverse effects.Based on the present data, it is hardly justified to recom-mend intrathecal opioids if the only purpose is to im-prove intraoperative analgesia.

The most important clinical question that emergesfrom the present review is whether the postoperativepain relief benefit of intrathecal morphine is worth theside effects. Unfortunately, it was not possible to de-scribe the impact of intrathecal morphine on postoper-ative pain in the same quantitative fashion as on adverseeffects. This was not because of a lack of raw data per se,but rather because of the fact that the various original

articles were dissimilar with respect to their outcomeparameters. Furthermore, no clear doseresponse rela-tionship relating to analgesic efficacy was observed intwo studies that investigated more than one dose ofmorphine.9,12 However, univariate logistic regressionanalysis showed that the relative risk of postoperativepruritus, nausea, and vomiting increased with increasingdoses of morphine.

It seems relatively clear from the qualitative analysisthat 0.1 mg intrathecal morphine results in at least 11 hof effective analgesia and a significant reduction in post-operative analgesic requirements. The question thus re-main whether such benefits are worth pruritus, nausea,and vomiting in a significant number of patients? Theestimated incidences of these adverse effects may beconsidered very high. However, it should be recognizedthat our analysis may overestimate the clinical signifi-cance of the various adverse effects, because these wereevaluated by presence or absence and not by severity.

Delayed respiratory depression is the most feared sideeffect of intrathecal opioids, and its true incidence is notknown. In a prospective study of 856 patients given 0.2mg intrathecal morphine for cesarean section, 8 hadrespiratory depression, as defined by a respiratory rateof , 8 breaths/min or an oxygen saturation of , 85%.27

Respiratory depression was observed in only 1 of 485patients in the present review. However, the calculatedNNH for respiratory depression (476; 95% CI, 164`)does not contribute much to our knowledge of respira-tory depression after intrathecal opioids.

Variation in Occurrence of Events and Quality ofReportsIt is well recognized that the incidence of events in a

comparison group can vary widely between studies.4 Verylow or very high event rates may influence the overallestimate of efficacy or harm.28 In the qualitative analysis oftime to first postoperative analgesic, event rates variedwidely in the control group. In contrast, the average con-trol event rates of adverse effects (table 2) were all withina narrow range. Consequently, comparisons between thevarious opioids and doses were not substantially con-founded by event rates far from the average.

The randomized controlled studies considered in thepresent review had median quality scores of 3 (range,25). It has been shown that the results of a metaanalysisare influenced by the quality of the primary studiesincluded. Trials of poor quality tend to exaggerate theoverall estimate of treatment effect and may lead to

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DAHL ET AL.


incorrect inferences.29 Consequently, trials with a scoreof , 2 were not included in this review.

Conclusion

There is evidence that intrathecal morphine produceda clinically relevant reduction in postoperative pain andanalgesic consumption; however, there is only evidencefor a small effect with fentanyl and sufentanil. Logisticregression analysis showed that the relative risk of bothpostoperative pruritus and nausea/vomiting increased ina dose-dependent manner with morphine. Based on thecurrent evidence, we recommend 0.1 mg morphine asthe drug and dose of choice. However, for every 100women receiving 0.1 mg intrathecal morphine added toa spinal anesthetic, 43 patients will experience pruritus,10 will experience nausea, and 12 will experience vom-iting postoperatively, all of whom would not have expe-rienced these adverse effects without treatment.

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