JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Tucker, A. P. Articles by Goodchild, C. S. Search for Related Content PubMed PubMed Citation Articles by Tucker, A. P. Articles by Goodchild, C. S. Related Collections Critical Care Obstetrics Pharmacology

---

PAIN MEDICINE

Intrathecal Midazolam II: Combination with Intrathecal Fentanyl for Labor Pain

From the Department of Anaesthesia, Monash Medical Centre, Victoria, Australia

Address correspondence and reprint requests to Adam P. Tucker, MBChB, DA, DRACOG, FANZCA, Department of Anaesthesia, Monash Medical Centre, 246 Clayton Road, Victoria 3168, Australia. Address email to adam.tucker{at}med.monash.edu.au

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Recent investigations have sought to improve intrathecal analgesia by combining opioids with other classes of analgesics. In this study we assessed the ability of intrathecal midazolam to increase the potency and duration of the analgesic effects of intrathecal fentanyl without causing adverse effects. Thirty parturients with cervical dilations 2–6 cm were randomized to receive either intrathecal midazolam 2 mg, fentanyl 10 µg, or both combined to initiate analgesia. Pain scores were recorded before and at 5-min intervals for 30 min after the injection and then every 30 minutes until the patient requested further analgesia. The presence and severity of nausea, emesis, pruritus, headache, and sedation, in addition to arterial blood pressure, heart rate, respiratory rate, sensory changes to ice, motor impairment, cardiotocograph, and Apgar score were also recorded. The parturients were assessed after 2 days and 1 mo for neurologic impairment. Preinjection pain scores were unaltered by intrathecal midazolam alone and moderately decreased by fentanyl. Intrathecal midazolam increased the analgesic effect of fentanyl. No treatment altered cardiorespiratory variables or caused motor impairment. The addition of intrathecal midazolam to fentanyl did not increase the occurrence of any maternal adverse event or abnormalities on the cardiotocograph. We conclude that intrathecal midazolam enhanced the analgesic effect of fentanyl without increasing maternal or fetal adverse effects.

IMPLICATIONS: Treatment of labor pain with epidural injections of local anesthetic is complicated by decreases in arterial blood pressure and leg weakness. This study showed that a mixture of two drugs, fentanyl and midazolam, could provide powerful pain relief when the drugs were given together spinally without such side effects.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Regional analgesia is the treatment of choice for severe labor pain. The advantage of regional analgesia compared with systemic opioids and inhaled anesthetics include higher quality pain control and reduced adverse fetal effects (1). Whereas bolus doses of regional analgesics are short-acting, continuous epidural analgesia via an indwelling catheter allows the maintenance of long-term analgesia. In contrast to continuous intrathecal analgesia, the combination of a bolus intrathecal injection coupled with a continuous epidural infusion has been widely used. Large surveys investigating the combined spinal-epidural (CSE) technique have shown it to be safe and effective (2). CSE results in a faster onset of analgesia and less motor blockade, although some authors have considered that these improvements are only applicable to limited clinical settings (3,4). However, a randomized observational study of 197 parturients found that women were more satisfied with the CSE analgesia compared with epidural analgesia (5).

Although local anesthetic blockade is effective in the management of severe pain, it causes vasodilation and, subsequently, hypotension in the mother. Furthermore, the potential loss of lower limb and pelvic muscle power can affect the bearing down reflex and result in muscle relaxation, which require the use of oxytocin. As knowledge of the nociceptive processes in the spinal cord has grown, so too has the possibility of the use of regional analgesics other than local anesthetics. Such drugs that do not cause hypotension or muscle paralysis that have been advocated by some authors include morphine, pethidine, fentanyl, and sufentanil, as well as intrathecal fentanyl and sufentanil (6,7). However, neuraxial opioids may cause sedation, respiratory depression, nausea, emesis, pruritus, and in some circumstances may cause fetal compromise (8).

Novel intrathecal non-opioid drugs have therefore been investigated in the management of labor pain. Clonidine and neostigmine have both been studied. Clonidine has been shown to produce antinociception when administered intrathecally but it has also been associated with hypotension and sedation (9). The use of intrathecal neostigmine has been associated with nausea and vomiting (10). In the non-obstetric setting, intrathecal midazolam produced segmental antinociception in rats and humans, but published clinical experience with this drug given intrathecally is limited (11–14).

Some of the preclinical literature has focused on the potential association between intrathecal midazolam and markers of neurotoxicity. Whereas the majority of these studies have not associated neurotoxicity with intrathecal midazolam (15–20), some studies have described adverse effects in large proportions (up to half) of the subject animals studied (21–24). The current clinical usage of intrathecal midazolam has therefore provided investigators the opportunity to determine whether this phenomenon occurs in patients or is primarily a preclinical laboratory finding. The results of a cohort study of 1100 patients investigating adverse neurological effects of intrathecal anesthesia with or without intrathecal midazolam has found no association between intrathecal midazolam and neurologic symptoms (25). Therefore, this study was conducted to investigate the efficacy of intrathecal midazolam. Specifically, this study tested the hypothesis that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in laboring parturients. The term "potentiation" was used to describe the effect of a drug being increased by the concurrent action of another drug at a dose that does not have an effect alone. In additional, the incidence of adverse effects was assessed in the patients who received intrathecal midazolam in addition to fentanyl.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
After institutional ethics committee approval, we studied sixty parturients requesting regional analgesia in early labor. Inclusion criteria included ASA physical status I–II, early active labor (cervical dilation 2–6 cm), a full-term singleton fetus (37–42 wk) with a vertex presentation, and a normal fetal heart rate (FHR) tracing. Patients were excluded from the study if they had difficulty understanding English, were younger than 18 yr of age, had a contraindication to an intrathecal injection, or had an allergy to any of the study drugs. Patients were also excluded if they had significant coexisting systemic or antenatal disease, such as antenatal hypertension, preeclampsia, or diabetes. Parturients were excluded if they had received other forms of analgesia within the preceding hour, had a history of chronic pain, or recently ingested medications that modified pain perception.

To optimize each patient’s ability to make an informed choice regarding entry into the trial, information regarding the trial was published in a booklet and given to all women attending antenatal classes. In the labor ward, only women with an accompanying adult were recruited to the study. The study was discussed and written information was supplied using language with a Flesch-Kincaid readability level of grade 10. A description of the serious risks of neurological damage was included. Written consent was obtained only after the information was read by both the parturient and the accompanying adult and a short time was allowed for both adults to discuss the study alone.

Each patient was randomized to receive either preservative-free intrathecal midazolam (Hypnovel 2 mg; Roche, Basel, Switzerland), fentanyl (Sublimase 10 µg; Janssen, Titusville, NJ), or both combined, as part of a CSE technique. The dose of fentanyl was chosen from earlier dose-response studies of its effect on labor pain (26,27). Ten micrograms of fentanyl was chosen because of its association with a modest analgesic effect and minimal side effects such as pruritus and nausea. Two milligrams of intrathecal midazolam was chosen because of a lack of adverse effects associated with its use as demonstrated by a large prospective cohort study (25).

Each parturient was hydrated with 500 mL of Hartmann’s solution IV and placed in the sitting position. An 18-gauge Tuohy and a 27-gauge pencil-point spinal needle were used (CSEcure 100/491/718; Portex, Hythe, UK). The epidural space was located at the vertebral level of L2-3 or L3-4 using the loss of resistance to air technique. A single space needle-through-needle technique was used to position the tip of the spinal needle in the intrathecal space. After the free flow of cerebrospinal fluid had confirmed the intrathecal location, a single injection of the study drug was given slowly over 10 s. The study drug was diluted in normal saline to a total volume of 2 mL in all cases. After the intrathecal injection, the spinal needle was withdrawn and the epidural catheter was threaded 3–5 cm into the epidural space. The catheter was then flushed with 2 mL of normal saline over 10 s to prevent later catheter occlusion. The parturient was placed into the supine position with left uterine displacement once the epidural catheter had been secured. No analgesic or local anesthetic drugs were administered through the catheter until the patient requested supplemental pain relief.

Data were collected by a research assistant who, in common with the patient, was unaware of the nature of the study drug. Pain scores were recorded immediately before and at 5-min intervals after the intrathecal injection using a verbal 11-point numerical rating score (NRS) (0 = no pain, 10 = worst pain imaginable) and a 10 cm visual analog score (VAS) (0 mm = no pain, 100 mm = worst pain imaginable). The occurrence and severity of the side effects were assessed at the same times, in addition to 2 assessments (15 and 30 min after injection) of segmental changes in sensation to ice and alteration of motor function using a modified Bromage score published previously (28).

During this investigation, a blinded observer asked the patient to grade the intensity of nausea, pruritus, and headache using a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe) after administration of the study drugs. The number of times a parturient vomited since the previous assessment was also recorded. In the event of vomiting or the presence of any of these symptoms, the patient was offered treatment. Sedation was rated by the observer using a four-point scale (1 = responds readily to name spoken in a normal tone, 2 = lethargic response to name spoken in a normal tone, 3 = responds only after name is called loudly or repeatedly, and 4 = responds only after mild prodding or shaking). The measurement of the parturients arterial blood pressure, heart rate, and respiratory rate was performed manually. Hypotension was defined as a systolic blood pressure <100 mm Hg or a 20% decrease from baseline and was treated with a fluid bolus and IV ephedrine as required.

Uterine contractions were monitored by external tocodynamometry and the FHR was monitored by external Doppler or fetal scalp clip. The cardiotocograph (CTG) was assessed by Fetal Monitoring Unit technicians who were unaware of the nature of the administered study drug. The CTG trace for 30 min after the intrathecal injection was examined. The definitions of CTG changes used by this unit were adopted unchanged for the purposes of this study. Therefore, a FHR of 120–160 bpm was considered normal and baseline variability of 6 bpm was considered normal. Normal fetal reactivity was described as FHR accelerations of 15 bpm lasting for 15 s and occurring twice or more every 20 min. These were signs of fetal well being. Periodic changes that are commonly considered to signify hypoxia include late FHR deceleration (FHR <120 bpm) that occurs later than 10 s after the start of a contraction and within 30 s after the end of a contraction. Early FHR decelerations occur concurrently with uterine contractions and variable fetal heart rate decelerations are not apparently related to the timing of uterine contractions. The causes of these two patterns of decelerations are thought to be increased vagal tone coincident with fetal skull compression and umbilical cord compression respectively. Variable decelerations may be classified as mild (the FHR remains more than 80 bpm) and severe (FHR <60 bpm). Therefore, the occurrence of late FHR decelerations was chosen as the primary marker of fetal distress. The Apgar scores were measured by the attending midwife who was unaware of which study drug had been administered to the mother.

Patients were informed that the intrathecal injection might take as long as 15 min to reach its maximum effect. The patient’s participation was considered complete if she requested further pain relief after 15 min. The parturient was permitted to withdraw from the study at any time from the time of enrollment. On request for further analgesia, an epidural local anesthetic block was instituted using the indwelling epidural catheter and the patient was managed according to normal clinical routine for the remainder of her labor.

The parturients were examined for any neurological symptoms 2 days after the intrathecal injection. The presence of back, leg, or buttock pain, in addition to the presence of leg numbness or weakness, was assessed. Other symptoms, including urinary incontinence or difficulty emptying the bladder, faecal incontinence or difficulty emptying the bowel, anogenital numbness or burning, and the presence of a headache, were also sought. A telephone assessment was conducted 1 mo later to detect symptoms with a delayed onset and to monitor the course of symptoms that were present at 48 h.

Statistical calculations were conducted using SPSS for Windows (Release 10.0.7). The demographic and obstetric variables were presented as proportions or mean ± SD and were analyzed by one-way analysis of variance (ANOVA) and the ² test as appropriate. The variation of rostral segmental sensory changes seen within each group was analyzed by grouping the number of parturients with sensory changes within evenly spaced dermatomal bands (T_12-11, T_10-9, T_8-7, and T_6-5) and testing the difference in the proportions between the study groups using the ² test. The pain scores (NRS and VAS) were analyzed by nonparametric tests on all occasions. The data were expressed as medians and the interquartile range (25th–75th percentiles). The correlation between the scores was tested with Spearman’s rank correlation. The lowest median pain score recorded by a study group after the intrathecal injection was compared with the median baseline pain score of the same group using a single Wilcoxon’s signed-ranks test. The NRS recorded from the combination drug group and the fentanyl group was compared for the same time period using a single Mann-Whitney U-test. The time to request supplemental analgesia was analyzed with the Student’s t-test. The comparison of the changes in the cardiorespiratory variables between the intrathecal fentanyl group and the midazolam-fentanyl group were tested using one-way ANOVA. The occurrence of adverse effects were presented in a tabular form for the reader’s own consideration where the numbers of patients affected were small and were tested by the ² test where the numbers were sufficiently large. The type I error rate was controlled by the Ryan-Holm step-down Bonferroni procedure where indicated. P 0.02 was regarded as statistically significant during the interim analysis.

	Results

Top Abstract Introduction Methods Results Discussion References

 
An interim analysis was scheduled a priori for the data provided by 30 of the 60 patients. After testing the primary end-points (the pain scores and the time to the request for supplemental analgesia) the study was halted because of an obvious effect of the combination therapy and a final analysis was performed. Of the 30 parturients who were enrolled into the study, 11 were randomly assigned to receive intrathecal fentanyl alone, 9 to receive intrathecal midazolam alone, and 10 to receive both drugs in combination.

The groups did not differ with respect to age, weight, ASA physical status, parity, gestation, cervical dilation, or the proportion of patients in each group who received oxytocin (Table 1). A segmental sensory change to ice was unable to be determined in five patients (three in the fentanyl, one in the midazolam, and one in the combination group). There was no significant difference in the distribution of the segmental levels achieved among the patients in the three groups (P = 0.87).

The maximal reduction of NRS among the parturients who received midazolam monotherapy occurred 5 min after the intrathecal injection and was not statistically significant (Fig. 1). In contrast, the maximum decrease in NRS after fentanyl occurred after 10 min, and although it was highly statistically significant (P = 0.007), the extent of the decrease in the NRS was modest (5/10). Although the 2 mg of midazolam alone was ineffective, when it was added to fentanyl a large reduction of the NRS resulted after 10 min that was both statistically significant (P = 0.005) and clinically successful (2/10). Comparison of the fentanyl monotherapy group with the combination group showed that the pain relief score was significantly lower in the combination group after 10 min (P = 0.02). Consistent results were found when the subgroup that reported VAS data was studied using the same method. Specifically, midazolam given alone did not cause a significant decrease in VAS, and its combination with fentanyl reduced the VAS at 10 min more so than fentanyl alone (P = 0.01).

View larger version (12K): [in this window] [in a new window]   Figure 1. The time response of numeric rating score of pain to IT midazolam, fentanyl, and the combination. The numerical rating scores of pain (NRS) are plotted against time. A, the maximum NRS depression after IT midazolam (2 mg) occurred 5 min after the injection and was not significantly different from the baseline value (P = 0.11). B, the maximum NRS depression after IT fentanyl (10 µg) occurred 10 min after the injection and was significantly lower than the baseline score (P = 0.007). C, the maximum depression of the NRS after the combination occurred 20 min after the injection; however, NRS at 10 min was compared with baseline pain score so that the effect of fentanyl and the combination treatments could be compared directly. The mild reduction of the NRS at 10 min was significantly less than the baseline NRS (P = 0.005). This pain score was also significantly lower compared with the pain score recorded 10 min after IT fentanyl alone (P = 0.02). Each point represents the median ± the interquartile range. The symbol ns denotes nonsignificance (P > 0.05) and ** denotes (P 0.01).

View larger version (9K): [in this window] [in a new window]   Figure 2. The time response of numeric rating score of pain to IT midazolam, fentanyl, and the combination. The times taken for the members of the study groups who received either fentanyl alone or fentanyl and midazolam combined to request supplemental analgesia are plotted. The average time for the members of the fentanyl group to request analgesia was 38 min as compared with the fentanyl-midazolam group, which averaged 92 min (P = 0.003). Each point represents a single parturient. The average of each study group is represented by a short horizontal line.

The addition of intrathecal midazolam to fentanyl did not confer any additional adverse effect as demonstrated by CTG trace and neonatal Apgar scores. Normal baseline variability was absent in 2 neonates (1 in the fentanyl group and 1 in the combination group; 95% confidence interval [CI], –0.17–0.19) and normal reactivity was absent for 9 (5 in the fentanyl group and 4 in the combination group; 95% CI, –0.50–0.42). Four neonates exhibited severe variable decelerations (3 in the fentanyl group and 1 in the combination group; 95% CI, –0.35–0.22). The number of neonates who were graded with the same Apgar scores was similar for both the fentanyl monotherapy group and the drug combination group (Table 3). All neonates scored 9–10 at 5 min after delivery.

One parturient reported persistent right leg pain and weakness subsequent to an antenatal fall, which resolved after 1 mo. A parturient who received intrathecal fentanyl alone recalled "sore legs" at the 1-mo assessment that had occurred for "a few days" postpartum before resolving spontaneously.

Several patients recalled leg numbness and weakness at the assessment 2 days postpartum. However these symptoms occurred in association with epidural local anesthetic infusions and all had resolved by the time of the assessment. A member of the fentanyl group reported de novo leg weakness at 1 mo, specifically, weakness of the toes bilaterally that made walking upstairs difficult. The symptoms resolved 12 mo later.

Bladder and bowel function were commonly affected. The most common complaint was constipation, which tended to resolve over time. After 1 mo, one parturient in each of the fentanyl and the combination groups had mild constipation. These symptoms resolved completely within 6 mo.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The addition of intrathecal midazolam to intrathecal fentanyl resulted in clinically relevant potentiation of analgesia. This was demonstrated by a larger decrement in pain scores (to a median NRS of less than 3) and prolongation of the duration of analgesia when the combination was compared with fentanyl alone. These two measures of efficacy may represent the same phenomenon as has been suggested with preclinical work (29). That is, it is likely that, having produced more profound analgesia with the combination, a longer time is required for the patient to approach the pain threshold again under the same conditions of dissipation of fentanyl.

Unfortunately, labor is commonly associated with neurological sequelae irrespective of the use of regional anesthesia. The birthing process is said to result in a 5-fold increase in neurological complications compared with the risk of neurological complications after regional anesthesia (30). Back pain is a frequent consequence of labor irrespective of the intervention of regional techniques. A randomized and controlled study of 369 women concluded that 20%–35% of parturients report backache at 3 months postpartum and 16%–35% report backache after 1 year (31). Other studies have reported a more frequent incidence of backache soon after delivery (43%–53% day one postpartum) with a tendency to diminish over time (32). The incidence of backache seen in this investigation was consistent with that reported in the medical literature.

Headache was also commonly seen in this investigation and did not appear dependent on any of the study drugs used. The incidence of postpartum headaches has been associated with the use of the loss of resistance to air technique for locating the epidural space as well as dural puncture (33).

The small sample size used in this study cannot establish the safety of the use of intrathecal midazolam. However, the incidence of adverse events was not more than the incidence of adverse events reported in the medical literature after childbirth nor in the fentanyl group and in all cases, resolution of the symptoms occurred over time.

We conclude that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in laboring parturients. It is most likely that this enhanced drug action occurs because of the combined action of two receptor-based systems in the spinal cord that may both act in concert to provide profound analgesia. This approach to pain therapy may hold the promise that favorable outcomes such as successful analgesia may be achieved without an increase in the occurrence of adverse effects such as pruritus and nausea. Further work aimed at the co-activation of the endogenous opioid and the gamma-aminobutyric acid A benzodiazepine spinal systems may provide new methods of improving current analgesic techniques to the benefit of our patients.

	Acknowledgments

 
The authors gratefully acknowledge Helen Barr for her assistance in the preparation of this study, Jenni Hogan and Sue Ho for their assistance with data collection, and Tattersalls for their financial support of the Monash University Department of Anesthesia.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Bergeret S, Loffredo P, Bosson JL, et al. Prospective national survey on alternatives to obstetrical peridural analgesia [in French]. Ann Fr Anesth Reanim 2000; 19: 530–9.[ISI][Medline]
2. Albright GA, Forster RM. The safety and efficacy of combined spinal and epidural analgesia/anesthesia (6,002 blocks) in a community hospital. Reg Anesth Pain Med 1999; 24: 117–25.[ISI][Medline]
3. Eisenach JC. Combined spinal-epidural analgesia in obstetrics. Anesthesiology 1999; 91: 299–302.[ISI][Medline]
4. Weiskopf RB. Clinical concepts and commentary. Anesthesiology 1999; 91: 6–7.[ISI][Medline]
5. Collis RE, Davies DW, Aveling W. Randomised comparison of combined spinal-epidural and standard epidural analgesia in labour. Lancet 1995; 345: 1413–6.[ISI][Medline]
6. Stocks GM, Hallworth SP, Fernando R, et al. Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl. Anesthesiology 2001; 94: 593–8.[ISI][Medline]
7. Gautier PE, De Kock M, Fanard L, et al. Intrathecal clonidine combined with sufentanil for labor analgesia. Anesthesiology 1998; 88: 651–6.[ISI][Medline]
8. Friedlander JD, Fox HE, Cain CF, et al. Fetal bradycardia and uterine hyperactivity following subarachnoid administration of fentanyl during labor. Reg Anesth 1997; 22: 378–81.[ISI][Medline]
9. Chiari A, Lorber C, Eisenach JC, et al. Analgesic and hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage of labor: a dose-response study. Anesthesiology 1999; 91: 388–96.[ISI][Medline]
10. Owen MD, Ozsarac O, Sahin S, et al. Low-dose clonidine and neostigmine prolong the duration of intrathecal bupivacaine-fentanyl for labor analgesia. Anesthesiology 2000; 92: 361–6.[ISI][Medline]
11. Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology 1990; 73: 273–7.[ISI][Medline]
12. Batra YK, Jain K, Chari P, et al. Addition of intrathecal midazolam to bupivacaine produces better post-operative analgesia without prolonging recovery. Int J Clin Pharmacol Ther 1999; 37: 519–23.[ISI][Medline]
13. Goodchild CS, Noble J. The effects of intrathecal midazolam on sympathetic nervous system reflexes in man-a pilot study. Br J Clin Pharmacol 1987; 23: 279–85.[ISI][Medline]
14. Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain 1992; 48: 5–12.[ISI][Medline]
15. Auroy P, Schoeffler P, Maillot C, et al. Intrathecal tolerability of midazolam: histological study [in French]. Ann Fr Anesth Reanim 1988; 7: 81–2.[Medline]
16. Bahar M, Cohen ML, Grinshpoon Y, et al. An investigation of the possible neurotoxic effects of intrathecal midazolam combined with fentanyl in the rat. Eur J Anaesthesiol 1998; 15: 695–701.[ISI][Medline]
17. Nishiyama T, Matsukawa T, Hanaoka K. Acute phase histopathological study of spinally administered midazolam in cats. Anesth Analg 1999; 89: 717–20.[Abstract/Free Full Text]
18. Schoeffler P, Auroy P, Bazin JE, et al. Subarachnoid midazolam: histologic study in rats and report of its effect on chronic pain in humans. Reg Anesth 1991; 16: 329–32.[ISI][Medline]
19. Schwieger IM, Jorge-Costa M, Pizzolato GP, et al. Intrathecal midazolam reduces isoflurane MAC and increases the apnoeic threshold in rats. Can J Anaesth 1994; 41: 144–8.[Abstract/Free Full Text]
20. Serrao JM, MacKenzie JM, Goodchild CS, Gent JP. Intrathecal midazolam in the rat: an investigation of possible neurotoxic effects. Eur J Pharmacol 1990; 7: 115–22.
21. Bozkurt P, Tunali Y, Kaya G, Okar I. Histological changes following epidural injection of midazolam in the neonatal rabbit. Paediatr Anaesth 1997; 7: 385–9.[ISI][Medline]
22. Erdine S, Yucel A, Ozyalcin S, et al. Neurotoxicity of midazolam in the rabbit. Pain 1999; 80: 419–23.[ISI][Medline]
23. Malinovsky JM, Cozian A, Lepage JY, et al. Ketamine and midazolam neurotoxicity in the rabbit. Anesthesiology 1991; 75: 91–7.[ISI][Medline]
24. Svensson BA, Welin M, Gordh T Jr, Westman J. Chronic subarachnoid midazolam (Dormicum) in the rat: morphologic evidence of spinal cord neurotoxicity. Reg Anesth 1995; 20: 426–34.[ISI][Medline]
25. Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg 2004; 98: 1512–20.[Abstract/Free Full Text]
26. Herman NL, Choi KC, Affleck PJ, et al. Analgesia, pruritus, and ventilation exhibit a dose-response relationship in parturients receiving intrathecal fentanyl during labor. Anesth Analg 1999; 89: 378–83.[Abstract/Free Full Text]
27. Palmer CM, Cork RC, Hays R, et al. The dose-response relation of intrathecal fentanyl for labor analgesia. Anesthesiology 1998; 88: 355–61.[ISI][Medline]
28. Lee BB, Ngan Kee WD, Hung VY, Wong EL. Combined spinal-epidural analgesia in labour: comparison of two doses of intrathecal bupivacaine with fentanyl. Br J Anaesth 1999; 83: 868–71.[Abstract/Free Full Text]
29. Yanez A, Sabbe MB, Stevens CW, Yaksh TL. Interaction of midazolam and morphine in the spinal cord of the rat. Neuropharmacology 1990; 29: 359–64.[ISI][Medline]
30. Durbridge J, Holdcroft A. The long-term effects of analgesia in labour. Baillieres Clin Obstet Gynaecol 1998; 12: 485–98.[ISI][Medline]
31. Howell CJ, Kidd C, Roberts W, et al. A randomised controlled trial of epidural compared with non-epidural analgesia in labour. BJOG 2001; 108: 27–33.[Medline]
32. Macarthur A, Macarthur C, Weeks S. Epidural anaesthesia and low back pain after delivery: a prospective cohort study. BMJ 1995; 311: 1336–9.[Abstract/Free Full Text]
33. Aida S, Taga K, Yamakura T, et al. Headache after attempted epidural block: the role of intrathecal air. Anesthesiology 1998; 88: 76–81.[ISI][Medline]

This article has been cited by other articles:

				Y. K. Batra, R. Mahajan, S. Kumar, S. Rajeev, and M. Singh Dhillon A Dose-Ranging Study of Intraarticular Midazolam for Pain Relief After Knee Arthroscopy Anesth. Analg., August 1, 2008; 107(2): 669 - 672. [Abstract] [Full Text] [PDF]

				M. A. Duncan Labour pains Can Fam Physician, January 1, 2008; 54(1): 28 - 29. [Full Text] [PDF]

				S. L. Shafer Anesthesia & Analgesia's Policy on Off-Label Drug Administration in Clinical Trials Anesth. Analg., July 1, 2007; 105(1): 13 - 15. [Full Text] [PDF]

				J. P. Rathmell, T. R. Lair, and B. Nauman The Role of Intrathecal Drugs in the Treatment of Acute Pain Anesth. Analg., November 1, 2005; 101(5S_Suppl): S30 - 43. [Abstract] [Full Text] [PDF]

				K. Jarbo, Y. K. Batra, and N. B. Panda Brachial plexus block with midazolam and bupivacaine improves analgesia: [Le bloc du plexus brachial avec du midazolam et de la bupivacaine ameliore l'analgesie] Can J Anesth, October 1, 2005; 52(8): 822 - 826. [Abstract] [Full Text] [PDF]

				S. K. Lin More on the Dilemma of Intrathecal Midazolam Anesth. Analg., February 1, 2005; 100(2): 604 - 604. [Full Text] [PDF]

				A. P. Tucker, J. Mezzatesta, R. Nadeson, and C. S. Goodchild Intrathecal Midazolam: Adverse Effects and Sources of Bias Anesth. Analg., February 1, 2005; 100(2): 605 - 605. [Full Text] [PDF]

				G. A. Van Norman, S. K. Palmer, and S. H. Jackson The Ethical Role of Medical Journal Editors Anesth. Analg., February 1, 2005; 100(2): 603 - 604. [Full Text] [PDF]

				L. Walker Intrathecal Midazolam: Adverse Effects and Sources of Bias Anesth. Analg., February 1, 2005; 100(2): 604 - 605. [Full Text] [PDF]

				M. J. Cousins and R. D. Miller Intrathecal Midazolam: An Ethical Editorial Dilemma Anesth. Analg., June 1, 2004; 98(6): 1507 - 1508. [Full Text] [PDF]

				T. L. Yaksh and J. W. Allen Preclinical Insights into the Implementation of Intrathecal Midazolam: A Cautionary Tale Anesth. Analg., June 1, 2004; 98(6): 1509 - 1511. [Full Text] [PDF]

				T. L. Yaksh and J. W. Allen The Use of Intrathecal Midazolam in Humans: A Case Study of Process Anesth. Analg., June 1, 2004; 98(6): 1536 - 1545. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Tucker, A. P. Articles by Goodchild, C. S. Search for Related Content PubMed PubMed Citation Articles by Tucker, A. P. Articles by Goodchild, C. S. Related Collections Critical Care Obstetrics Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999