Spinal opioids in the management of obstetric pain

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SpinalOpioids in the Management of ObstetricPain .Ronald J. Hurley, MD, and Mark D. Johnson, MD Deparbnent of Anesthesia, Brigham and Won&s Hospital, Harvard Medical School,

Boston, Xwachusetts

Spinal opioids have become increasingly pop&r age& for providing analgesia during ha&or,augmenting anesthesiu during cesarean section, and providingpain relief after o@rativedelivery. The development of spinal opioti in the management of obstetrk painisreviewed. J Pain Symptom Mana?? 1990;5:146-153.

Ke) words Obstetric pain, spinal

ids, labor, cesarian section, postpartum pain

After Queen Victoria accepted chloroform anesthesia during the delivery of Prince Leopold, the concept of pain relief during childbirth became more socially accepted. Opioids have been used to provide pain relief for thousands of years and a wide variety of these drugs have heen employed in an attempt to provide analgesia for childbirth. However, until recently, even marginally effective pain relief for labor required relatively large parenteral doses that were often associated with maternal/fetal sedation and respiratory depression. The discovery of opioid receptors in the spinal cord presented the intriguing possibility that narcotic agonists could be locally administered to specific receptors to produce analgesia, while minimizing systemic effects. Such an approach has theoretic advantages for the pregnant patients, as it might significantly reduce fetal exposure to opioids. A&m r$riilltrequeslsto: Ronald Hurley,MD, Department of Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston, MR 02115. @ U.S.Gamer Pain Relief Comtrktee, 1990 Published by Elsevier, New York, New York

In 1979, Behar’ first used epidural morphine clinically, and Wang* reported the use of subarachnoid morphine. Studies on the effects of epidural opioids in the pregnant patient followed in rapid succession. The epidural route has been especially attractive as the incidence of postlumbar puncture headache has increased in pregnant patients and epidural local anesthetics are being used with increasing frequency for labor. Extensive animal and human studies have not demonstrated neurotoxicity with any commercially available, preservative-free opioid agent administered via the epidural or spinal routem Epidural opioids appear to exert most of their effect on receptors in the substantia gelatinosa of the spinal c~rd.*~~ Presumably, epidurally administered opioids reach these receptors via the cerebrospinal fluid (CSF), following direct penetration of the dura, as well as by passing around nerve root sleeves.3 Opioids given via the epidural space also diffuse into the systemic circulation with resultant measurable blood concentrations comparable to levels seen with intramuscular parenteral administration. The

O&x35-3924/90/$3.50

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Managemmt of ObstetricP&a

rate at which these processes occur depends upon the physical-chemical properties of the opioid (eg, rate is directly proportional to lipid solubility, and inversely proportional to molecular weight).3 Clinically, opioids can be classified as lipid insoluble (eg, morphine), which tend to have a delayed onset of action and long duration of effect, or lipid soluble (eg, fentanyl), which tend to have shorter onset times, but shorter duration of effect. The clinical epidural/subarachnoid ratio-that is, the dose of opioid required to exert a clinical effect when given via the epidural route as compared to the subarachnoid route-is -’ LOto 1 for morphine. Morphine is not rapidly taken up into tissue following intraspinal administration, and a slow cephalsd spread in the cerebrospinal fluid can occur; this can result in delayed respiratory depression. Fentanyl, which is 600 times more lipid soluble than morphine, has a clinical epidural/subarachnoid ratio of -3 to I. Since it is bound tightly Within the central nervous system (CNS), there is minimal CSF redistribution and, thus, minimal risk of respiratory depressions Nevertheless, when fentanyl is administered epidurally, significant plasma levels occur that can approach those observed after parenteral administration. Nausea, vomiting, pruritus, and urinary retention are side effects that can occur with any mu agonist, given by the epidural or subarachnoid route. Often, these side effects can be managed with small intravenous (IV) doses of naloxone, which usually can be titrated to relieve the side effects without antagonizing anal‘gesia. Butorphanoi, a kappa agonist, given epidurally, causes minimal nausea and pruritus, and may actually be useful epidurally in combination with mu agonists to minimize these side effects.6 Clinically effective epidural doses of morphine or fentanyl result in small but detectable blood levels of opioid. Comparable doses of opioid given epidurally instead of parenterally produce more profound analgesia and are of Thus, smaller doses given greater duration. less often can be used. This minimizes peak maternal plasma levels and resultant fetal exposure. The recent resurgence of interest in the subarachnoid route for opioids in labor may further reduce this fetal exposure.

147

livq Spinal opioids for the management of l&or pain, either alone or in combination with local anesthetics, may provide analgesia without causing motor and sympathetic block.

In 1979, Vaksh’ reported that intrathecal morphine produced analgesia in pregnant rats. Early reports of intrathecal morphine in humans for labar were enthusiastic and controversiak6 It soon became clear that subarachnoid morphine, while useful in early labor, did not consistently provide adequate pain relief for the second stage.gJO Subarachnoid morphine was also associated with a high incidence of side effects, including somnolence, severe pruritus, and nausea and vomiting. Mowever, Brookshire” found that an intravenous infusion of nafoxone could significantly reduce the side effects without inhibiting the analgesia provided by 1 mg of intrathecal morphine. The use of intrathecal morphine without combination with local anesthetics has found limited application for the relief of labor pain in recent years. For example, Abboudt* reported the successful use of 1 mg of preservative-free morphine with 7.5% dextrose in a parturient with severe pulmonary hypertension, where pain relief without sympathetic blockade was essential. The goal of providing labor analgesia with a single dose of intrathecal opioid is laudable, and other efforts have been made. Subarachnoid opioid administradon may eventually prove to be a simple method of providing at least partial analgesia for labor in hospitals where conventional epidural coverage is unavailable or impractical. LeightotP recently reported the use of a combination of intrathecal morphine and fentanyl. Theoretically, the fentanyl should provide rapid onset and, morphine, prolonged duration of analgesia. She administered 0.25 mg t$ morphine with 25 f.t,gof fencanyl through a single dural puncture early in the first stage of iabor. Analgesia was achieved in <5 min and lasted until delivery (3-3.5 hr) in 60% of the patients. The remaining 40% ultimately required conventional lumbar epidural analgesia with local anesthetics. The risk of delayed respiratory depression limits increasing the dose

448

Hurlq, and Jthmn

of intrathecd morphine to prolong further the duration of analgesia. Perhaps a safer and more controllable approach would utilize continuous subarachnoid infusion of a highly lipid soluble agent such as fentanyl, through an iutrathecal catheter. However, until recently, only relatively large catheter ( 19 and 20 gauge) and needle (17 and 18 gauge) combinations were available. Dural punctures with these needles were associated with a prohibitively high rate of postlumbar puncture headache. In 1989, the Food and Drug Administration ap proved a Se-garage polyimide catheter for continuous spinal anesthesia. This microcatheter (Microspinal TFX Medical, Duluth, GA) is compatible with the lumen of a standard 25- to 26gauge spinal needle. The authors used one of these microcatheters to provide labor analgesia with subarachnoid meperidine for a patient with a history of allergy to amide and ester local anesthetics. Meperidine is apparently unique in that it has some local anesthetic as well as spinal opioid receptor activity.‘* Perineal surgeryI and cesarean sectio# have been performed with subarachnoid meperidine alone. Oyama,” in 1980, reported the use of synthetic 8-endorphin administered intrathecalllp to women in labor. The results were amazing. Labor pain in all 14 patients disappeared completely within 3-4 min and this analgesia lasted 12-32 hr. Side effects were minimal, and all infants appeared normal. The relatively large size (3,300 daltons) of B-endorphin limited diffusion through the dura and necessitated subarachnoid placement of the drug. Subarachnoid administration may be advantageous, however, since it risks little or no transmission to the fetus. Unfortunately, the cost of the drug is prohibitive, and appropriate toxicity testing should be accomplished before further studies are done. While the intrathecal route for labor analgesia is not frequently used by the clinician today, the future of this approach for relief of labor pain with spinal opioids or opioid-local anesthetic combinations appears bright.

Ep&Jural0$0&& Administration of opioids via the epidural space for labor is becoming increasingly popular. The effect of epidural opioids is complicat-

Journal of Pain and Symptom Management

ed by the need for the drug to cross the dura and by the presence of a rich venous plexus, which absorbs the chug and is often distended secondary to the inferior vena cava obstruction associated with pregnancy. Perhaps as a consequence of these effects, the use of epidural opioids alone has generally proven to be of limited utility as a labor analgesic.‘sJg However, :hey are useful in combination with local anesthetics. A4o@&e. As the only currently approved opioid for intraspinal use, morphine is a logical choice for combination with bupivacaine for labor analgesia. Niv et a12*added 2 mg of epidural morphine to 0.25% bupivacaine and significantly increased the duration of analgesia before reinforcement. Pruritus was the only significant side effect observed, and no neonatal depression was seen. Morphine’s slow onset (30-60 min) and relatively high incidence of side effects (pruritus, nausea, and potential respiratorv depression) will likely prevent widespread clinical acceptance of this technique. Butoqthanol. Butorphanol, a kappa agonist and weak mu agonist-antagonist, is a commonly administered opioid for labor, which has been demonstrated to be quite safe. Hunt” suggested that 2 mg of butorphanol added to 8.5-10 mL 0.25% bupivacaine was the optimal dose. The duration of analgesia was significantly greater and the time to onset of analgesia significantly shorter than when no butorphanol was added. The most common maternal side effect was somnolence. Care must be taken not to administer this drug to patients who are physically dependent on opioids, since this agoniet-antagonist drug may precipitate an acute withdrawal syndrome even when given epidurally.** Alfatanil and Sufmkmil. As might be expected, sufentanil and alfentanil are now being studied as combinations with bupivacaine in labor. Heytens used epidural alfentanil alone in 16 primiparous patients at an infusion rate of 30 kg/kg/hi-, with boluses of 30 pglkg as needed. Excellent pain relief was rapidly obtained in early labor, but analgesia was inadequate for the latter part of stage I and stage II. The Amiel-Tison neonatal neurobehavioral exam revealed significant hypotonia. A preliminary

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reportz4 suggests that combining lower-dose alfentanil with bupivdcaine can provide excellent analgesia for labor and no detectable neonatal depression. Sufentanil should be attractive theoretically because of its very high lipid solubility and affinity for the mu receptor. Van Steea$erge25 and Phillips26 showed that suferztanil in combination with bupivacaine provtded prolonged analgesia, reduced the total bupivacaine dose, and limited motor blockade. However, in the epidural space, sufentanil appears to be only 2-3 times more potent than fentanyl, while systemically it is 5- 10 times more potent. Therefore, accidental intravascular injection of 30 p,g of sufentanf would be likely to cause respiratory depression. Van Steenberge did find epidural sufentanil to he associated with maternal dizziness and lowered l-minute Apgar scores that may indicate systemic absorption. Sufentanil is also associated with significantly more pruritus and nausea, and is more expensive than fentanyl. The most popular narcotic for use in labor is undoubtedly fentanyl. Justins2’ in 1982 added 80 pg of fentanyl to 3 mL of 0.5% bupivacaine. Since then Youngstrom in 1984, Skerman?g Vella,3O and Cnhe# in 1987 and Cellanos2 and ChestnutS in 1988 have touted the efficacy of the combination. Bupivacaine concentrations as low as 0.028% combined with 100 kg of fentanyl have proven to be analgesic. Respondents to a recent survey at the annual meeting of the Society for Obstetric Anesthesia and Perinatology indicated that 56% used epidural opioids for labor, with the vast majority favoring fentanyl. The solutions most popular were 50- 100 pg of fentanyl in 10 mL of bupivacaine 0.25% or 0.125%. About 20% of the respondents used fentanyl in an infusion; the preferred solution was fentanyl l-2 kg/mL in bupivacaine 0.125% that was administered at rates of 8- 10 mWhr.

FentmpL

Subarachmid

i$iG&

Intrathecal morphine has been used successfully in many types of surgery, including cesarean delivery. A high incidence of side effects,

149

including life threatening respiratory depression, can be seen if doses >0.5 mg are used. ChadwicP concluded that subarachnoid marphine sulfate in doses of 0.3-0.5 mg provided similar postoperative analgesia to 3-5 mg of epidural morphine but with greater duration and no greater side effects. Two especially interesting reports in 1988 by; Abboudss and Abou1eishs6 showed that 0.1, 0.2, and 0.25 mg morphine mixed with hyperbaric bupivacaine provided excellent postoperative analgesia and may cause less respiratory depression than standard subcutaneous morphine injection. Hunts’ showed that fentanpl in doses as low as 6.25 Fg is also an effective intrathecal adjunct that provides effective postoperative analgesia for 3-4 hr.

Epidural morphine, fentanyl, and butorphanol have been studied for cesarean delivery (Table 1). Hughesa reported 1,700 consecutive patients having received epidural morphine with excellent long lasting postoperative analgesia. Four patients were noted to have respiratory depression, two required treatment with naloxone, and one was seriously acidotic. The issue of monitoring patients after intraspinal morphine is controversial. Fentanyl is the most popular opioid for epidural use with cesarean delivery. Fentanyl appears to be very safe with 50 p.g lasting -2-3 hr.3g The 50 pg of fentanyl should be diluted in at least 10 mL of preservative free normal saline for fastest onset and longest durationem Epidural fentanyl augments intraoperative anesthesia with epidural bupivacaine41 or lidocaine4* and may reduce the incidence of peripartum shivering.43 Thus, it is advantageous to give the epidural fentanyl (prior to fetal delivery) once the epidural block has been established. An additional dose of 50 pg of fentanyl in 10 enL of normal saline can be given postoperativeIy just prior to removal of the epidural catheter to provide several hours of analgesia aff.er the resolution of the local anestl:etia.Mock. While the effects of epidural lidacaine and bupivacaine41A2 are additive with epiduml fenmnyl, 2-chloroprocaine is antagonistic. Malinow and colleagueP found no clinically significant period of fentanyl analgesia after 3% 2-chloroprocaine was used with epidurals for

HUT&~and Johnson

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Table 1 Doses of Subarachnoid and Epidural Opioids for Cesarean Delivery and Postoperative Pain Relief Dose

Onset (min)

Duration (hr)

Subarachnoid Morphine sulfate Fentanyl

0.3 mg 15 lJ,g

30-45 5

12- 15 2-4

Epidural Morphine sulfate Fentanyl Sufentanil Butorphanol

3mg 50 &lo cc NS 30-50 pg/lO cc NS l-2 mg

45-60 5 3-5 10-15

12-18 2-3 2-4 3-5

low pH delivery. Chloroprocaine’s (3.3-3.5) or some secondary metabolite may be responsible for this interaction. Epidural sufentanil has also been studied in cesarean delivery patients. In doses of 30-50 pg diluted in 10 mL of preservative free normal saline, this drug provides analgesia with onset and duration similar to fentanyl.45 At clinically effective doses, it is associated with a greater incidence of nausea and pruritus than fentanyl.37 Interestingly, in epidural doses of a50 pg, it can abolish shivering and effect maternal trmperature control in a dose dependent fashcesarean

ion_4%44-46

Epidural sufentanil appears to offer little advantage over fentanyl in the setting of cesarean delivery, and it presents significantly greater risk. Should the epidural catheter inadvertently become intravascular, a dose of 30-50 u,g of sufentanil could precipitate respiratory depression or chest wall rigidity. Epidural butorphanol, in doses of l-2 mg,4s has also been studied in postcesarean section patients. It has an onset of 15-20 min and a duration of 3-4 hr. It has not been associated with pruritus or significant respiratory depression. In fact, NaultyG reported on the uses of an epidural butorphanoYfentany1 combination to minimize fentanyl’s side effects. Epidural butorphanol can produce some maternal sedation and may affect fetal monitoring. Thus, it may be most useful for postoperative analgesia after the fetus is delivered.

Toxicity and @bud Of&ids The CAYiderahle advantages of spinal

Fetal

opioids brust always be weighed against the pas-

sibility of fetal depression. Drugs administered to the mother are transported rapidly to the uterus, and the concentrations of free drug available to cross the placenta will depend on the agent, total dose, route of administration, lipid solubility, pKa, maternal pH, protein binding, metabolism, and excretion.3 All commercially available narcotics have low molecular weights and readily cross die placenta by diffusion.4g Although there is an extensive literature concerning maternal effects of spinal morphine, evaluation of the infant has most often been confined to Apgar scores or the occurrence of apnea. Subtle elfects of drugs on the neonate require subtle neurologic tests. However, most investigators would agree that the risk of neonatal depression with epidural morphine appears to increase with higher doses and shorter interval between dosing and delivery time because of higher maternal blood levels of morphine.s* The prolonged onset, the high incidence of maternal side effects, and the risk of delayed respiratory depression have limited the use of the epidural morphine in laboring patients. Fentanyl has an impressive safety record. Neonatal depression has only been reported with very high repeated epid:ural doses. When administered by the cpidural route, fentanyl produces peak plasma levels similar to that produced by the same dose given intramuscularly. Gaffud and colleagues41 administered 100 l.~gof fentanyl epidurally -20 min before cesarean delivery. Theoretically, this should produce near-maximal fetal exposure. They found that 100 pg of epidural fentanyl resulted in an average umbilical artery concentration of 0.8 pg/mL. This is below the concentration impli-

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Management qf ObstetricPain

cated in respiratory depression of the newborn.51 In another study, the optimal dose of epidural fentanyl in the parturient was determined to be 50 F~O in 10 mL of normal saline, which should minimize fetal exposure and possible depres,sion. Phillips*‘j has compiled much of the data regarding the use of epidural sufentanil. Undetectable levels in maternal venous and umbilical cord bloti are consistent with sufentanil’s very high lipid solubility. Overall, 156 parturients received sufentanil with only one study reporting a decrease in the mean Apgar scores. Unfortunately, neurobehavioral testing of the neonate has not been reported. While the published, evaluations are few, alfentanil has been asso,:iated with neonatal de-

pression. Heytens and colleagues2s continuously infused epidural alfentanil alone and stopped at the onset of the second stage 01 labor. Although Apgar scores and umbilical blood gas values were normal, the neurologic and adaptive capacity scores showed significant depression of active and passive tone. Again, subtle effects require subtle evaluation. More recent work using much lower doses of alfentanil is promising.52 Butorphanol in epidural doses of l-2 mg is not usually associated with respiratory depression. Thus far, neonatal depressiorl has not been seen. However, butorphanol given via epidural or other parenteral routes is associated with particular fetal heart rate patterns. A lowamplitude, high-ffequency sinusoidal pattern has been noted after drug injection.53 The pattern usually resolves spontaneously and is usually associated with normal fetal scalp capillary pH samples.

Although morphine is the only opioid presently approved for epidural or subarachnoid use, fentanyl appears to be the safest currently available opioid agent for spinal use. At the Brigham and Women’s Hospital, over 6,000 doses of spinal fentanyl (epidural and subarachnoid) have been given without significant side effects. The risks associated with intraspinal morphine appear to be higher; indeed, prudent management of patients receiving spinal morphine requires close attention to respiratory function for at least 24 hr.

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Spinal opioids have limited application when used alone for labor analgesia. They are very usefu! in combination with local anesthetics and cm provide excellent analgesia with minimal mo!ipar block. Specifically, spinai opioids i,m augment local anesthetic regional anesthesia for cesarean delivery and provide postoperative analgesia with the duration varying with the agent used. The epiduraii route for administration of these solutions is dominant in obstetric anesthetic services today, but the future of subarachnoid infusion techniques appears promising.

eferences 1. Behar M, Magora F, Olshwang D, Davidson JT. Epidural morphine in treatment of pain. Lancet 1979;1:527. 2. Wang JK. Nauss LE, Thomas JE. Pain relief by intrathecally applied morphine in man. Anestbesiology 1979;50:149-151. 3. Cousins MJ, Mather LE. Intrathecal and epidural administravron of opioids. Anesthesiology 1984;6 1: 27G-310. 4. Calvillo 0, Henry JL, Neuman RS. Effects of morphine and naloxone on dorsal horn neurons in the cat. Can J Physiol Pharmacol 1974;52: 1207- 1211. 5. Ketahata LM, Kosaka Y. Taub A. Lamina-specific suppression of dorsal horn unit activity by morphine sulfate. Anesthesiology 1974;41:39-48. 6. Naulty JS, Labove P, Datta S, Hunt CO, Ostheimer GW. Epidural butorphanol/fentrnyl for post-cesarean delivery analgesia. Anesthesiology 1987;67:A463. 7. Yaksh TL, Wilson RP, Kaiko RF, lnturrisi CE. Analgesia produced by a spinal action of morphine and effects upon parturition in the rat. Anesthesiology 1979;51:386-392. 8. Alper MH. Intrathecal morphine: a new method of obstetric analgesia? Anesthesiology 1979;51:378379. 9. Scott PV, Bowen FE, Cartwright P, et al. Intrathecal morphine as sole analgesic during labour. Br Med J 1980;2:351-353. 10. Baracca A, Noueihed R, Haj S. lntrathecal injection of morphine for obstetric analgesia. Anestbesiology 1981;54:136-140. 11. Brookshire GL, Shnider SM, Abboud TK, et al. Effects of naloxone on the mother and neonate after intrathecal morphine for labor analgesia. Anesthesiology 1983;59:A417. 12. Abboud TK, Raya J, Noueihed R, Daniel J. Intrathecal morphine for relief of labor pain in a partuient with severe pulmonary hypertension. Anesthesiology 1983;59:477-479.

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13. Leighton BL, DeSimone CA, Norris MC, BenDavid B. Intrathecal narcotics revisited: the combination of fentanyl and morphine intrathecally provides rapid onset of profound, prolong& analgesia. Anesth Analg 1989;69:122- 125. 14. Fan;ewo CE, Naguiob M. Spinal anaemhesia with meperidine as the sole agent. Can Anaesth SOCJ 1985;32:533-537. 15. Acalouschi I, Ene V, Lorinezi E, Nicholaus F. Saddle block with pethidine for perineal operations. Br J Anaesth 1986;58:1012-1016. 16. Talafre M, Jacquinot P, Leganeux F, Jasson J, Consiller C. Intrathecal administration of meperidine versus tetracaine for elective cesarean section. Anesthesiology 1987;67:A620. 17. Oyama T, Matsuki A, Taneichi T, Ling N, Guiollemin R. Beta-endorphin in obstetric analgesia. Am J Obstet Gynecol 1980;137:613-616. 18. Husemeyer RP, O’Connor MC, Davenport HT. Failure of epidural morphine to relieve pain in labour. Anaesthesia 1980;35:161-163.

Journal of Pain and Symptm Mrtnagement

29. Skerman JH, Thompson BA, Goldstein MT, Jacobs MA, Gupta A, Blass NH. Combined continuous epidural fentanyl and bupivacaine in labor: a randomised study. Anesthesiology 1985;63:A450. 30. Vella LM, Willatts DG, Knott C, Lintin DJ, Justins DM, Reynolds F. Epidural fentanyl in labour. Anaesthesia 1985;40:742-747. 31. Cohen SE, Tan S, Albright GA, Halpem J. Epidural fentanyFbupivacaine for obstetric analgesia. Anesthesiology 1987;67:403-407. 32. Cellano D, Capogna G. Epidural fentanyl plus bupivacaine 0.125 per cent for labour: analgesic effects. Can J Anaesth 1988;35:375-378. 33. Chestnut DH, Owen CL, Bates JN, Ostman LG, Choi WW, Geiger MW. Continuous infusion epidural analgesia during labor: a randomized, double-blind comparison of 0.0625% bupivacainef0.0002% fentanyl versus 0.125% bupivacaine. Anesthesiology 1988;68:754-759.

19. Writer WDR, James FM, Wheller AS. Double blind comparison of morphine and bupivacaine for continuous epidural analgesia in labor. Anesthesiology 1981;54:215-219,

34. Cahdwick HS, Ready LB. Intrathecal and epidural morphine sulfate for post cesarean analgesia. Anestheliiology 1988;68:925-929. 35. Ab i3ud TK, Dror A, Mosaad P, et al. Mini-dose 9 intrathecal morphine for the relief of postcesarean section pain. Anesth Analg 1988;67:370-374.

20. Niv D, Rudick V, Golan A, Chayen MS. Augmentation of bupivacaine analgesia by epidural morphine. Ohstet Gynecol 1986;67:206-209.

36. Abouleish E, Rawal N, Fallon K, Hernandez D. Combined morphine and bupivacaine for cesarean section. Anesth Analg 1988;67:370-374.

21. Hunt CO, Naulty JS. Malinow AM, Datta S, Ostheimer GW. Epidural hutorphanol-bupivacaine for analgesia during labor and delivery. Anesth Analg 1989;68:323-327.

37. Hunt CO, Naulty JS, Bader AM, et al. Perioperative analgesia with suharachnoid fentanyl-bupivaCaine. Anesthesiology 1987;67:A621.

22. Weintraub SJ, Naulty JS. Acute abstinence drome after epidural injection of butorphanol. esth Analg 1985;64:452-453.

synAn-

23. Heytens L, Cammu H. Camu F. Extradural analgesia using alfentanil. Br J Anaesth 1987;59:331337. 24. Carp H, Johnson MD, Bader AM. Continuous epidural infusion of alfemanil and bupivacaine for labor and delivery. Anesthesiology 1988;69:A687. 25. Van Steenberge A, DeBroux HC, Noorduin H. Extradural bupivacaine with sufentanil for vaginal delivery: a double-blind trial. Br J Anaesth 1987; 59:1518- 1522. 26. Phillips G. Continuous infusion of epidural analgesia in labor: the effect of adding sufentanil to 0.125% bupivacaine. Anesth Analg 1988;67:462465. 27. Justins DM, Francis D, Houlton PG, Reynolds F. A controlled trial of extradural fentanyl in labour. Br J Anaesth 1982;54:409-414. 28. Youngstrom P, Sedensky M, Frankmann D, Spagnuolo S. Continuous epidural infusion of lowdose bupivacalne-fentanyl for labor analgesia. Anesthesiology 1988;69:686.

38. Hughes SC. Intraspinal narcotics in obstetrics. Clin Perinatol 1982;l: 167- 175. 39. Naulty JS, Datta S, Ostheimer GW. Johnson MD, Burger GA. Epidural fentanyl for postcesarean delivery pain management. Anesthesiology 1985;63:694698. 40. Birnbach DJ, Johnson MD, Arcario T, Datta S, Naulty JS, Ostheimer GW. Effects of diluent volume on analgesia produced by epidural fentanyl. Anesth Analg 1989;68:808-810. 41. Gaffud MP, Bansal P, Lawton C, Velasquez N, Watson WA. Surgical analgesia for cesarean delivery with epidural bupivacaine and fentanyl. Anesthesiology 1986;65:331-334. 42. Preston PG, Rosen MA, Hughes SC, et al. Epidural anesthesia with fentanyl and lidocaine for cesarean section: maternal effects and neonatal outcome. Anesthesiology 1988;68:938-943. 43. Matthews NC. Epidural fentanyl for shaking in obstetrics. Anaesthesia 1988;43:783-785. 44. Malinow A, et al. Anesthetic choice affects postcesarean epidural fentanyl analgesia. Reg Anaesth 1988;13:86. 45. Tan S, Cohen SE, White PF. Sufentanil for analgesia after cesarean section: intravenous versus epidural administration. Anesth Analg 1986;65:S158.

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46. Rosen MA, Dailey PA, Hughes SC, et al. Epidural sufentanil for postoperative analgesia after cesarean section. Anesthesiology 1988,68:448-454. 47. Sevarino FB, Johnson MD, Lema MJ, Datta S, Ostheimer GW, Naulty JS. The effect of epidural sufentanil on shivering and body temperature in the parturient. Anesth Analg 1989;68:530-533. 48. Hunt CO, Naulty JS. Malinow AM, Datta S, Ostheimer GW. Epidural hutorphanol-bupivacaine for analgesia during labor and delivery. Anesth Analg 1989;68:323-327. 49. Hug CC. Pharmacokinetics of new synthetic narcotic analgesics. In: FG Estafanous, ed. Opioids in anesthesia. Boston: Butterworth, 1984:52.

I53

50. Nybell-Lindahl G, Carisson C, Ingemarsson I, et al. Maternal and fetal concentrations of morphine after epidural administration during labor. Am J Obstet Gyynecol 1981;139:20-21. 51. Mikon D, Bentue-Ferrer D, Noury D, et al. Anesthesie peridurale pour cesarienne par association bupivacaine-fentanyl. Ann Fr Anesth Reanim 1983; 2:273-279. 52. Ray NL, Datta S, Johnson MD. Continuous infusion of epidural bupivacaine with fentanyl or alfentanil. SOAP Abstr 1989. 53. Hutjis CG, Meis PJ. Sinusoidal fetal heart rate pattern associated with butorphanol administration. Obstet Gynecol 1986;65:377-380.