Some research has shown the usefulness of intrathecal clonidine in urology procedures, although there are some controversies. In a controlled, prospective, double-blind investigation with patients undergoing elective transurethral resection of bladder tumours under spinal anaesthesia [47] the authors found that adding clonidine 75 µg to prilocaine 75 mg increased the duration of sensory and motor block and reduced the need for additional postoperative analgesics by providing excellent analgesia for about 8 hours during recovery period. In a similar study, 25 µg spinal clonidine improved bupivacaine spinal anaesthesia: shorter time to achieve complete motor block and sensory block at T9 level, with longer postoperative analgesia. [48] In 60 patients undergoing transurethral resection of prostate or bladder tumors Kanazi et al [49] compared clonidine 30 µg, versus dexmedetomidine 3 µg added to 12 mg spinal hyperbaric bupivacaine, versus bupivacaine alone. Patients treated with alpha2 agonists had a significantly shorter onset time of motor block and significantly longer sensory and motor regression times than patients who only received local anaesthetic. The mean time of sensory regression to the S1 segment was 303 ±75 min for those injected with dexmedetomi‐ dine, 272 ±38 min in the group who received clonidine and 190±48 min in patients with bupivacaine alone (bupivacaine versus dexmedetomidine and bupivacaine versus clonidine, p< 0.001]. The regression of motor block to Bromage 0 was 250 ±76 min, 216±35 min, and 163±47 min respectively (bupivacaine versus dexmedetomidine and bupivacaine versus clonidine, p< 0.001]. The onset and regression times were not significantly different between patients treated

in the saline and

Postoperative pain following orthopaedic surgeries has been shown to be a significant negative factor that delay patient recovery and contributes to serious complications. It may also result in larger use of healthcare resources and ultimately lead to poor outcomes. The utilization of multimodal pain management following large orthopaedic surgeries like total joint arthro‐ plasty, total knee replacement, or spinal surgery has positively affected the quality of postop‐ erative care, reduced surgical pain, and decreased the magnitude of opioid consumption and subsequent dose-related complications. Multimodal spinal anaesthesia-analgesia including spinal clonidine is safe and may reduce hospital stay, decrease postoperative complications, and increase patient satisfaction.

In a dose-response prospective study, Strebel et al [53] compared three doses of clonidine (37.5, 75 and 150 µg) added to spinal 0.5% bupivacaine 18 mg in 80 orthopaedics patients. Duration of sensory block (regression below level L1) was increased in patients receiving intrathecal clonidine: 311±101 min in 37.5 µg (+8%), 325 ±69 min in 75 µg (+13%), and 337±78 min in those patients who received 150 µg (+17%) (estimated parameter for dose 0.23 [95% confidence interval-0.05-0.50]). versus control group 288 ±62 min. Time to first analgesic request was also prolonged: 343 ±75 min (+16%), 381±117 min (+29%), and 445±136 min (+51%) (estimated parameter for dose 1.02 [95% confidence interval 0.59-1.45]), respectively compared to control group 295±80 min. Hemodynamic stability was maintained and they found no differences in sedation level. van Tuijl and coworkers [37] investigated the effect of 0, 15 and 30 µg of clonidine added to 5 mg hyperbaric bupivacaine on the duration of motor block, analgesia and ability to void after knee arthroscopy. They found that clonidine increased motor block duration by 25 and 34 min respectively. They also found better analgesic quality, and the mean time for spontaneous voiding was increased up to 18 and 44 min respectively. Amaranto and Berrío demonstrated that spinal clonidine 2 µg/kg added to hyperbaric lidocaine in orthopae‐ dic cases enhance anaesthesia quality, significantly prolonged post operative analgesia, with early motor recovery and minimal side effects. [54] In adolescents scheduled for lower extremities orthopaedic surgery under spinal anaesthesia with isobaric 0.5% bupivacaine added with clonidine 1 µg/kg prolonged duration of sensory and motor block, produced extended spinal postoperative analgesia by 120 min, without severe side effects. [55] Spinal sufentanil 75 µg alone, or added with epinephrine 200 µg, or clonidine 30 µg after total hip replacement results in good analgesia with similar onset and duration of action, and minor side effects. [56] Compared with intrathecal dexmedetomidine, clonidine had a similar results in patients undergoing lower limb surgery with spinal bupivacaine; Mahendru et al [57] conducted a prospective study adding clonidine 30 µg, vs. dexmedetomidine 5 µg, vs. fentanyl 25 µg to 12.5 mg spinal hyperbaric bupivacaine in cases of lower limb surgeries. They discov‐ ered that dexmedetomidine prolonged significantly sensory and motor block compared to clonidine, fentanyl and bupivacaine alone. The mean time of two segment sensory block regression was 147±21 min with dexmedetomidine, 117±22 with clonidine, 119±23 in those patients receiving fentanyl, and 102±17 in bupivacaine alone (p> 0.0001). The regression time of motor block to reach modified Bromage 0 was 275±25, 199±26, 196±27, 161±20 respectively (p > 0.0001). Hemodynamic stability was conserved. In patients 60 years or older undergoing lower extremity orthopaedic surgeries, intrathecally clonidine 15 µg or 30 µg with 9 mg hyperbaric bupivacaine, significantly potentiated the sensory block levels and duration of analgesia without affecting the trend of systolic blood pressure as compared to bupivacaine alone. Clonidine in doses of 30 µg however facilitated the ascent of sensory level block to unexpectedly higher dermatomes for a longer time. [58] Spinal postoperative analgesia can be improved by epidural infusion of 40 µg/h-1 mixed with ropivacaine 4 mg/h-1 in patients undergoing hip arthroplasty. [59]

section, and for postoperative pain relief. Its use tends to be more frequent in this field, since it reduces opioids doses, and thus the side effects such as emesis and maternal pruritus, and the possibility of respiratory depression secondary to rostral opioid distribution. Theoretically,

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*Labour analgesia.* There are many advances in the pharmacology of labour analgesia focused on alternatives mechanisms to target spinal pain receptors, and the efficacy and safety of old and new drugs and techniques; i.v. remifentanyl for patient controlled analgesia, low dose of diluted local anaesthetics, addition of neuraxial adjuvants like opioids, neostigmine, and

Most studied doses of intrathecal clonidine for labour analgesia range from 15 to 45 µg mixed with opioids and/or local anaesthetics. In a preliminary open-label protocol done in France by Mercier and coworkers [69] comparing sufentanil 5 µg+clonidine 30 µg versus sufentanil 5 µg alone injected intrathecally to alleviate pain during the first stage of labour, the authors demonstrated that clonidine potentiate labour analgesia and side effects such hypotension, maternal pruritus and sedation were similar in both groups. In a second research, the same group [70] studied 53 nulliparous women in painful labour using the same doses, but followed by 5 mg of epidural bupivacaine. In this study the duration of analgesia was longer in the sufentanil-clonidine group versus sufentanil alone [125±46 versus 97±30 min, p=0.007]. There were more incidents of hypotension and ephedrine needs in those patients who received sufentanil and clonidine. The incidence of fetal heart rate abnormalities during the first 30 min after spinal injection was similar in both groups [17% versus 19%). No parturient had motor blockade. Gautier et al [71] found that 30 µg of intrathecal clonidine plus 2.5 or 5 µg intrathecal sufentanil increased the duration of labour analgesia during the first stage without undesirable maternal or fetal effects. Labbene et al. [72] added clonidine 15 µg to 2.5 mg isobaric bupiva‐ caine and 5 µg sufentanil during combined spinal-epidural analgesia resulting in extended duration of analgesia without increasing side effects. In nonobstetrical patient doses of 25 to 30 µg of clonidine augmented duration of postoperative analgesia, so smaller dose of clonidine

Chiari et al from Austria [73] did the first study using spinal clonidine as a sole drug for labour analgesia; in 36 parturients with < 6 cm cervical dilation; they compared 50, 100, and 200 µg intrathecal clonidine and found that labour pain was significantly reduced in all patients, analgesia duration was significantly longer with 200 µg (median 143; range 75-210 min), with 100 µg (median 118; range 60-180 min) and using 50 µg (median 45; range 25-150 min). Hypotension was associated with 200 µg and the need of intravenous ephedrine more often

There are controversies in the use of spinal clonidine for labour analgesia as some researchers have found a higher frequency of maternal hypotension, foetal arrhythmia, and worse neonatal umbilical artery pH. Therefore, some of them do not recommend its use. [74, 75, 76] The study done by Paech et al [77] with subarachnoid fentanyl 20 µg+bupivacaine 2.5 mg, plus either saline or clonidine 15, 30 or 45 µg found that addition of clonidine to fentanyl-bupivacaine reduced maternal blood pressure and did not significantly augment the duration of spinal

it could also reduce the fetal bradycardia.

may be effective in the obstetric population.

than in the other groups.

clonidine. [65, 66, 67, 68]

Some studies have found conflicting data which showed that spinal clonidine is not a useful adjuvant for postoperative analgesia in orthopedic major surgery. Gehling et al [60] evaluated 45 patients undergoing hip or knee replacement under 15 mg bupivacaine spinal anaesthesia and found a mean time until first opioid request was for placebo 10.3±7.9 h, for 0.1 mg morphine 23.0±3.9 h and for 0.1 mg morphine+50 µg clonidine 21±6.9 h, respectively. Coadministration of pethidine 0.75 mg/kg-1 and clonidine 75 µg provided good intraoperative anaesthesia for total hip replacement, but similar to plain isobaric 0.5% bupivacaine. [61]

#### **11. Obstetrics**

The role of the anesthesiologist in obstetrics has many responsibilities; labour analgesia, anesthesia for vaginal delivery, anaesthesia for cesarean section, anaesthesia for non-obstetric surgeries during pregnancy, and postoperative analgesia. A comprehensive labour analgesia program has to include newer procedures and ajuvant drugs to facilitate ambulation, excellent pain relief, patient comfort and safety for the mother-fetus binomial. [62, 63, 64] Spinal clonidine has been used for labour analgesia, to enhance spinal anaesthesia during cesarean section, and for postoperative pain relief. Its use tends to be more frequent in this field, since it reduces opioids doses, and thus the side effects such as emesis and maternal pruritus, and the possibility of respiratory depression secondary to rostral opioid distribution. Theoretically, it could also reduce the fetal bradycardia.

time for spontaneous voiding was increased up to 18 and 44 min respectively. Amaranto and Berrío demonstrated that spinal clonidine 2 µg/kg added to hyperbaric lidocaine in orthopae‐ dic cases enhance anaesthesia quality, significantly prolonged post operative analgesia, with early motor recovery and minimal side effects. [54] In adolescents scheduled for lower extremities orthopaedic surgery under spinal anaesthesia with isobaric 0.5% bupivacaine added with clonidine 1 µg/kg prolonged duration of sensory and motor block, produced extended spinal postoperative analgesia by 120 min, without severe side effects. [55] Spinal sufentanil 75 µg alone, or added with epinephrine 200 µg, or clonidine 30 µg after total hip replacement results in good analgesia with similar onset and duration of action, and minor side effects. [56] Compared with intrathecal dexmedetomidine, clonidine had a similar results in patients undergoing lower limb surgery with spinal bupivacaine; Mahendru et al [57] conducted a prospective study adding clonidine 30 µg, vs. dexmedetomidine 5 µg, vs. fentanyl 25 µg to 12.5 mg spinal hyperbaric bupivacaine in cases of lower limb surgeries. They discov‐ ered that dexmedetomidine prolonged significantly sensory and motor block compared to clonidine, fentanyl and bupivacaine alone. The mean time of two segment sensory block regression was 147±21 min with dexmedetomidine, 117±22 with clonidine, 119±23 in those patients receiving fentanyl, and 102±17 in bupivacaine alone (p> 0.0001). The regression time of motor block to reach modified Bromage 0 was 275±25, 199±26, 196±27, 161±20 respectively (p > 0.0001). Hemodynamic stability was conserved. In patients 60 years or older undergoing lower extremity orthopaedic surgeries, intrathecally clonidine 15 µg or 30 µg with 9 mg hyperbaric bupivacaine, significantly potentiated the sensory block levels and duration of analgesia without affecting the trend of systolic blood pressure as compared to bupivacaine alone. Clonidine in doses of 30 µg however facilitated the ascent of sensory level block to unexpectedly higher dermatomes for a longer time. [58] Spinal postoperative analgesia can be improved by epidural infusion of 40 µg/h-1 mixed with ropivacaine 4 mg/h-1 in patients

Some studies have found conflicting data which showed that spinal clonidine is not a useful adjuvant for postoperative analgesia in orthopedic major surgery. Gehling et al [60] evaluated 45 patients undergoing hip or knee replacement under 15 mg bupivacaine spinal anaesthesia and found a mean time until first opioid request was for placebo 10.3±7.9 h, for 0.1 mg morphine 23.0±3.9 h and for 0.1 mg morphine+50 µg clonidine 21±6.9 h, respectively. Coadministration of pethidine 0.75 mg/kg-1 and clonidine 75 µg provided good intraoperative anaesthesia for total hip replacement, but similar to plain isobaric 0.5% bupivacaine. [61]

The role of the anesthesiologist in obstetrics has many responsibilities; labour analgesia, anesthesia for vaginal delivery, anaesthesia for cesarean section, anaesthesia for non-obstetric surgeries during pregnancy, and postoperative analgesia. A comprehensive labour analgesia program has to include newer procedures and ajuvant drugs to facilitate ambulation, excellent pain relief, patient comfort and safety for the mother-fetus binomial. [62, 63, 64] Spinal clonidine has been used for labour analgesia, to enhance spinal anaesthesia during cesarean

undergoing hip arthroplasty. [59]

**11. Obstetrics**

106 Topics in Spinal Anaesthesia

*Labour analgesia.* There are many advances in the pharmacology of labour analgesia focused on alternatives mechanisms to target spinal pain receptors, and the efficacy and safety of old and new drugs and techniques; i.v. remifentanyl for patient controlled analgesia, low dose of diluted local anaesthetics, addition of neuraxial adjuvants like opioids, neostigmine, and clonidine. [65, 66, 67, 68]

Most studied doses of intrathecal clonidine for labour analgesia range from 15 to 45 µg mixed with opioids and/or local anaesthetics. In a preliminary open-label protocol done in France by Mercier and coworkers [69] comparing sufentanil 5 µg+clonidine 30 µg versus sufentanil 5 µg alone injected intrathecally to alleviate pain during the first stage of labour, the authors demonstrated that clonidine potentiate labour analgesia and side effects such hypotension, maternal pruritus and sedation were similar in both groups. In a second research, the same group [70] studied 53 nulliparous women in painful labour using the same doses, but followed by 5 mg of epidural bupivacaine. In this study the duration of analgesia was longer in the sufentanil-clonidine group versus sufentanil alone [125±46 versus 97±30 min, p=0.007]. There were more incidents of hypotension and ephedrine needs in those patients who received sufentanil and clonidine. The incidence of fetal heart rate abnormalities during the first 30 min after spinal injection was similar in both groups [17% versus 19%). No parturient had motor blockade. Gautier et al [71] found that 30 µg of intrathecal clonidine plus 2.5 or 5 µg intrathecal sufentanil increased the duration of labour analgesia during the first stage without undesirable maternal or fetal effects. Labbene et al. [72] added clonidine 15 µg to 2.5 mg isobaric bupiva‐ caine and 5 µg sufentanil during combined spinal-epidural analgesia resulting in extended duration of analgesia without increasing side effects. In nonobstetrical patient doses of 25 to 30 µg of clonidine augmented duration of postoperative analgesia, so smaller dose of clonidine may be effective in the obstetric population.

Chiari et al from Austria [73] did the first study using spinal clonidine as a sole drug for labour analgesia; in 36 parturients with < 6 cm cervical dilation; they compared 50, 100, and 200 µg intrathecal clonidine and found that labour pain was significantly reduced in all patients, analgesia duration was significantly longer with 200 µg (median 143; range 75-210 min), with 100 µg (median 118; range 60-180 min) and using 50 µg (median 45; range 25-150 min). Hypotension was associated with 200 µg and the need of intravenous ephedrine more often than in the other groups.

There are controversies in the use of spinal clonidine for labour analgesia as some researchers have found a higher frequency of maternal hypotension, foetal arrhythmia, and worse neonatal umbilical artery pH. Therefore, some of them do not recommend its use. [74, 75, 76] The study done by Paech et al [77] with subarachnoid fentanyl 20 µg+bupivacaine 2.5 mg, plus either saline or clonidine 15, 30 or 45 µg found that addition of clonidine to fentanyl-bupivacaine reduced maternal blood pressure and did not significantly augment the duration of spinal labour analgesia. To avoid hypotension due to the combination of spinal clonidine-opioidsdiluted local anaesthetics, epidural clonidine can be used in doses of 75 µg. [78]

(18±12%). Sedation was significantly more intense compared to saline (p<0.05), also dried mouth was more commonly (p<0.01). Although these data suggest that 150 µg subarachnoid clonidine is effective to treat acute pain after cesarean section, it has side effects such as

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In a research [4] using 150, 350 and 450 µg of spinal clonidine performed to evaluate the doseresponse hemodynamic and analgesic profiles in the immediate postoperative period of cesarean section under general anaesthesia. The authors found that pain was less in all groups in a dose dependent mode: request for first analgesic 402±75 min, 570±76 min, and 864± 80 min respectively (p<0.01-0.001]. Clonidine reduced mean arterial pressure compared with baseline only in those patients treated with 150 µg (21±13%, p < 0.05). Sedation was evident in all groups. Respiratory rate and motor activity of the lower extremities were unaffected in all three groups. The hemodynamic stabilility after 300 and 450 µg suggested a pressor consequence at periph‐ eral sites. In an unpublished research we found that 75 µg of spinal clonidine was not enough

Spinal anaesthesia is safe and effective in children, with many advantages like minimal cardiorespiratory disturbances. Its major limitation is its short duration, which can be extended, as in adults, with the mixture of adjuvants drugs. [90, 91] In postnatal rats, spinal clonidine did not produce signs of neurotoxicity, [33] and has been used in all pediatric age groups, from newborns to teenagers. In newborns, Rochette and coworkers [92] studied 75 patients which were injected with increasing doses of clonidine (0.25, 0.5, 1 y 2 µg/kg) with plain spinal bupivacaine 0.5% (1 mg/kg) and concluded that clonidine 1 µg/kg produces improvement in spinal anaesthesia duration without significant side effects. Dose of 2 µg/kg produced transient hypotension. In a randomized investigation with 45 children aged 6 to 15 years, clonidine 2 µg/kg prolonged motor block and improved postoperative analgesia. Hypotension and bradycardia were 54% and 30% respectively. [93] In children aged 6-8 year undergoing spinal anaesthesia with 0.5% bupivacaine for orthopedic surgery, the addition of clonidine 1 µg/kg prolonged significantly the time to regression of the sensory block and recovery of motor block, also delayed time for first rescue analgesia. Sedation was augmented and propofol require‐ ment were reduced. [94] Batra et al [95] also demonstrated that intratecal clonidine 1 µg/kg

The term balanced spinal analgesia refers to the antinociceptive effect produced by the interaction between several drugs that injected inside the subarachnoid space would abolish or reduce the intensity of postoperative pain. Spinal non opioids adjuvants compounds have moderate to low analgesic potency, but combined with opioids allow a decrease of opioids

hypotension, sedation, and dryness of mouth.

to perform curettage in patients with incomplete abortion.

reduces propofol dose for sedation in children.

**13. Postoperative pain**

**12. Pediatrics**

When low doses of clonidine with or without opioids are used for spinal labour analgesia, we must remember that at the end of pregnancy there is a degree of autoanalgesia mediated by endorphins [79] Even though neuraxial analgesia is the most efficient and safest mode of labour analgesia, the use of spinal clonidine mixed with opioids and/or local anaesthetics must be used cautiously to avoid hypotension.

*Cesarean section.* Nowadays, spinal anaesthesia is the most used technique for cesarean section. [80] Currently, opioids are the drugs most commonly used as adjuvants in this clinical scenario, but its side effects are troubling. Low doses of spinal clonidine in cesarean section are used to improve the anaesthetic block, to reduce the dose of local anaesthetics, and to prolong postoperative analgesia. It can also be combined with intrathecal opioids, as there is a synergic effect as discussed in previous paragraph.

In a recent study, 37.5 µg of clonidine added to hyperbaric bupivacaine was suggested as the optimal dose for emergency cesarean surgery, allowing reduction of up to 18% of the total dose of hyperbaric bupivacaine. [81] Adding clonidine 75µg to hyperbaric bupivacaine prolongs spinal anaesthesia and improves early postoperative analgesia after cesarean section, but does not diminish morphine needs during the first 24 hours of the postoperative period. [82] Other studies have found that 75 µg is a safe dose; prolong the anaesthetic block and enhance postoperative analgesia, with minimal side effects and no harm to the newborn. [83, 84, 85] In a randomized, double blind, dose finding study, Peach et al [86] compared intrathecal clonidine mixed with fentanyl and morphine versus clonidine plus morphine in 240 women undergoing cesarean section with hyperbaric 0.5% bupivacaine. A dose-finding analysis showed similar postoperative efficacy and side effects for groups receiving morphine 100µg with clonidine 60, 90, or 150 µg and concluded that a multimodal approach to postcesarean analgesia, using subarachnoid bupivacaine, fentanyl, morphine 100 µg, and clonidine 60 µg, improves pain relief compared with morphine 100 µg or clonidine 150 µg alone, but increases intraoperative sedation and may increase perioperative vomiting. In another dose finding study [87] comparing 15 µg, 30 µg and 60 µg of clonidine added to hyperbaric bupivacaine 0.5%, the authors found a dose dependent variability of analgesia duration and sedation. Duration of analgesia was significantly higher in those patients who received clonidine 60 µg as compared to the other two groups (598.7±140.47 versus 436.65±149.84 and 387.1±97.05 minutes respectively). Sedation was also more in the highest dose. In this study the authors recommended 15 µg and 30 µg doses due to good postoperative analgesia and less sedation.

As a single drug, subarachnoid clonidine is not recommended neither for anaesthesia or post cesarean analgesia. In order to evaluate the analgesic effect of clonidine, a double blind study was carried out in 20 patients undergoing elective cesarean section; [88] 150 µg of spinal clonidine were injected 45 min after general anaesthesia and compared to intrathecal saline as control group. Pain intensity was lower in clonidine treated patients from 20 to 120 min after intrathecal injection (p< 0.05), request for first analgesic was also longer in the clonidine group 414±128 min versus 181±169 min (p< 0.01). Clonidine side effects were severe; hypotension with a maximal reduction of systolic (15±9%), diastolic (22±12%) and mean arterial pressure (18±12%). Sedation was significantly more intense compared to saline (p<0.05), also dried mouth was more commonly (p<0.01). Although these data suggest that 150 µg subarachnoid clonidine is effective to treat acute pain after cesarean section, it has side effects such as hypotension, sedation, and dryness of mouth.

In a research [4] using 150, 350 and 450 µg of spinal clonidine performed to evaluate the doseresponse hemodynamic and analgesic profiles in the immediate postoperative period of cesarean section under general anaesthesia. The authors found that pain was less in all groups in a dose dependent mode: request for first analgesic 402±75 min, 570±76 min, and 864± 80 min respectively (p<0.01-0.001]. Clonidine reduced mean arterial pressure compared with baseline only in those patients treated with 150 µg (21±13%, p < 0.05). Sedation was evident in all groups. Respiratory rate and motor activity of the lower extremities were unaffected in all three groups. The hemodynamic stabilility after 300 and 450 µg suggested a pressor consequence at periph‐ eral sites. In an unpublished research we found that 75 µg of spinal clonidine was not enough to perform curettage in patients with incomplete abortion.

#### **12. Pediatrics**

labour analgesia. To avoid hypotension due to the combination of spinal clonidine-opioids-

When low doses of clonidine with or without opioids are used for spinal labour analgesia, we must remember that at the end of pregnancy there is a degree of autoanalgesia mediated by endorphins [79] Even though neuraxial analgesia is the most efficient and safest mode of labour analgesia, the use of spinal clonidine mixed with opioids and/or local anaesthetics must be

*Cesarean section.* Nowadays, spinal anaesthesia is the most used technique for cesarean section. [80] Currently, opioids are the drugs most commonly used as adjuvants in this clinical scenario, but its side effects are troubling. Low doses of spinal clonidine in cesarean section are used to improve the anaesthetic block, to reduce the dose of local anaesthetics, and to prolong postoperative analgesia. It can also be combined with intrathecal opioids, as there is a synergic

In a recent study, 37.5 µg of clonidine added to hyperbaric bupivacaine was suggested as the optimal dose for emergency cesarean surgery, allowing reduction of up to 18% of the total dose of hyperbaric bupivacaine. [81] Adding clonidine 75µg to hyperbaric bupivacaine prolongs spinal anaesthesia and improves early postoperative analgesia after cesarean section, but does not diminish morphine needs during the first 24 hours of the postoperative period. [82] Other studies have found that 75 µg is a safe dose; prolong the anaesthetic block and enhance postoperative analgesia, with minimal side effects and no harm to the newborn. [83, 84, 85] In a randomized, double blind, dose finding study, Peach et al [86] compared intrathecal clonidine mixed with fentanyl and morphine versus clonidine plus morphine in 240 women undergoing cesarean section with hyperbaric 0.5% bupivacaine. A dose-finding analysis showed similar postoperative efficacy and side effects for groups receiving morphine 100µg with clonidine 60, 90, or 150 µg and concluded that a multimodal approach to postcesarean analgesia, using subarachnoid bupivacaine, fentanyl, morphine 100 µg, and clonidine 60 µg, improves pain relief compared with morphine 100 µg or clonidine 150 µg alone, but increases intraoperative sedation and may increase perioperative vomiting. In another dose finding study [87] comparing 15 µg, 30 µg and 60 µg of clonidine added to hyperbaric bupivacaine 0.5%, the authors found a dose dependent variability of analgesia duration and sedation. Duration of analgesia was significantly higher in those patients who received clonidine 60 µg as compared to the other two groups (598.7±140.47 versus 436.65±149.84 and 387.1±97.05 minutes respectively). Sedation was also more in the highest dose. In this study the authors recommended 15 µg and 30 µg doses due to good postoperative analgesia and less sedation. As a single drug, subarachnoid clonidine is not recommended neither for anaesthesia or post cesarean analgesia. In order to evaluate the analgesic effect of clonidine, a double blind study was carried out in 20 patients undergoing elective cesarean section; [88] 150 µg of spinal clonidine were injected 45 min after general anaesthesia and compared to intrathecal saline as control group. Pain intensity was lower in clonidine treated patients from 20 to 120 min after intrathecal injection (p< 0.05), request for first analgesic was also longer in the clonidine group 414±128 min versus 181±169 min (p< 0.01). Clonidine side effects were severe; hypotension with a maximal reduction of systolic (15±9%), diastolic (22±12%) and mean arterial pressure

diluted local anaesthetics, epidural clonidine can be used in doses of 75 µg. [78]

used cautiously to avoid hypotension.

108 Topics in Spinal Anaesthesia

effect as discussed in previous paragraph.

Spinal anaesthesia is safe and effective in children, with many advantages like minimal cardiorespiratory disturbances. Its major limitation is its short duration, which can be extended, as in adults, with the mixture of adjuvants drugs. [90, 91] In postnatal rats, spinal clonidine did not produce signs of neurotoxicity, [33] and has been used in all pediatric age groups, from newborns to teenagers. In newborns, Rochette and coworkers [92] studied 75 patients which were injected with increasing doses of clonidine (0.25, 0.5, 1 y 2 µg/kg) with plain spinal bupivacaine 0.5% (1 mg/kg) and concluded that clonidine 1 µg/kg produces improvement in spinal anaesthesia duration without significant side effects. Dose of 2 µg/kg produced transient hypotension. In a randomized investigation with 45 children aged 6 to 15 years, clonidine 2 µg/kg prolonged motor block and improved postoperative analgesia. Hypotension and bradycardia were 54% and 30% respectively. [93] In children aged 6-8 year undergoing spinal anaesthesia with 0.5% bupivacaine for orthopedic surgery, the addition of clonidine 1 µg/kg prolonged significantly the time to regression of the sensory block and recovery of motor block, also delayed time for first rescue analgesia. Sedation was augmented and propofol require‐ ment were reduced. [94] Batra et al [95] also demonstrated that intratecal clonidine 1 µg/kg reduces propofol dose for sedation in children.

#### **13. Postoperative pain**

The term balanced spinal analgesia refers to the antinociceptive effect produced by the interaction between several drugs that injected inside the subarachnoid space would abolish or reduce the intensity of postoperative pain. Spinal non opioids adjuvants compounds have moderate to low analgesic potency, but combined with opioids allow a decrease of opioids dose for postoperative pain control, resulting in less opioids side effects, promoting recovery and faster home readiness. Spinal alpha2 agonist drugs are not used routinely as a single analgesic in the postoperative period. A single dose of spinal clonidine as a sole postoperative analgesic has poor effect. When clonidine is added to spinal local anaesthetics or spinal opioids it does extend the time to first analgesic dose and decrease the total amount of systemic postoperative opioids. Clonidine spinal synergism with other analgesics is due to antinoci‐ ceptive actions that have been described in previous paragraphs. In previous sections we have discussed some aspects of postoperative analgesia produced by intrathecal clonidine in various surgical scenarios. In this section we discuss more details on the prevention of postoperative pain with spinal clonidine.

that patients in the first group needed more intravenous fluid administration, have more bradycardia, but duration of analgesia was significantly larger than in the hyperbaric clonidine group (median, 400 min; range, 115-400 min versus median 265 min; range, 205-400 min. p <

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In conclusion, for postoperative pain the addition of clonidine to intrathecal local anaesthetics and/or opioids extends the time to first analgesia and decreases the amount of opioids used. Severe hypotension and bradycardia are seldom observed, and sedation is not an important

As reviewed, there is no universal agreement on recommended dose for the various clinical uses of spinal clonidine. Recently, Ginosar, Riley and Angst [105] did a nice study in volunteers and found out a clonidine dose dependant effect. Significant analgesia to experimental heat pain was detected above 25 µg. After 50 µg the heat pain tolerance increased by that ∼1°C, similar to the analgesic effect of 5 mg epidural morphine or 30 µg epidural fentanyl observed

Table 1 shows the different doses of intrathecal clonidine in different clinical scenarios of subarachnoid anaesthesia and analgesia. It can be seen that the dose range is wide as already discussed in this chapter. Up until today, there is not a standard recommended dose of subarachnoid clonidine. Doses range from 15 up to 450µg. It is necessary to adjust the dose to several factors: age, type of patients, time of surgery, type of surgery and dose of local

**Type of surgery Dose range µg Effects Reported side effects References** Ambulatory 15 to 150 Enhance anaesthesia quality Prolongs motor block [37, 38, 39] Postoperative analgesia Hypotension

General surgery 15 to 75 Enhance sensory and motor block Hypotension [41, 42, 43,

Urology 25 to 150 Shortens latency time Bradycardia [47, 48, 49,

50, 51] 4 µg/kg Retrace regression 2 segments/S1

incidence

consumption

segment

Postoperative analgesia Prevents postoperative hyperalgesia and chronic pain Decreases postoperative analgesic

44, 45, 46] Decrease trans operative pain

Sedation

Hypotension

0.05). Sedation scores did not differ between groups.

**14. Controversy over spinal clonidine dose**

in studies using this experimental heat pain model.

anaesthetic and intrathecal opioids used.

side effect.

Adding clonidine 150 µg to spinal bupivacaine in patients undergoing femoral osteosynthesis prolonged significantly the first request for analgesics compared to oral clonidine and plain spinal bupivacaine (337±29 min, 313±29 versus 236±27 min respectively), and reduced the total dose of morphine. [96] Combining 50 mg of hyperbaric lidocaine, 25 µg fentanyl, and clonidine 150 µg produced excellent postoperative analgesia in proctological patients. [97] Small doses of spinal clonidine also produce postoperative analgesia without deleterious side effects. In a comparative evaluation of 15 µg versus 30 µg clonidine as analgesic adjuvant added to 15 mg of spinal 0.5% hyperbaric bupivacaine in 90 patients undergoing abdominal hysterectomy, the authors [98] found a prolonged first pain complaint time for those women treated with clonidine compared with patients who did not received spinal clonidine (315.37+50.3, 387.07+83.19 versus 204.8+34.8 minutes). Hemodynamic parameters were alike in all patients.

A recent meta-analysis by Engelman and Marsala [99] found that clonidine increased the duration of postoperative analgesia by 1.63 h [95% confidence interval (CI): 0.93-2.33]. There was a 90% probability that clonidine increases the duration of postoperative analgesia by more than 75 min compared with morphine alone. They also found that spinal clonidine decrease the need for postoperative morphine by a mean of 4.45 mg. (95% CI: 1.40-7.49 mg). Hypoten‐ sion was the only side effect increased by clonidine (odds ratio 1.78; 95% CI: 1.02-3.12). In patients undergoing transurethral surgery, 25 µg clonidine plus 7.5 mg of subarachnoid isobaric bupivacaine significantly delayed time for first request supplemental analgesia compared to bupivacaine alone (434.1±78. 3 min versus 263.97±40.38 min p=0.000) respectively. [48] In a recent study done with clonidine 30 µg added to intratecal bupivacaine-fentanyl, the authors demonstrated that the incidence of intraoperative pain and postoperative analgesic requirements were significantly less compared with the patient who did not received the alfa2 agonist for vaginal hysterectomy. [100]

Chest pain after coronary artery bypass surgery has been relieved with intrathecal clonidine in doses 1 µg/kg or 100 µg, with or without spinal opioids. Adding clonidine to neuraxial opioids improves the quality of analgesia postoperatively and expedites the process of weaning from mechanical ventilation, allowing earlier extubation. No serious side effects have been described. [101, 102, 103]

Baker and coworkers [104] hypothesized that hyperbaric clonidine avoid its rostral migration, and consequently reduced some of its side effects such as hypotension, bradycardia and sedation. They use 150 µg of either isobaric or hyperbaric clonidine in 30 elderly patients found that patients in the first group needed more intravenous fluid administration, have more bradycardia, but duration of analgesia was significantly larger than in the hyperbaric clonidine group (median, 400 min; range, 115-400 min versus median 265 min; range, 205-400 min. p < 0.05). Sedation scores did not differ between groups.

In conclusion, for postoperative pain the addition of clonidine to intrathecal local anaesthetics and/or opioids extends the time to first analgesia and decreases the amount of opioids used. Severe hypotension and bradycardia are seldom observed, and sedation is not an important side effect.

#### **14. Controversy over spinal clonidine dose**

dose for postoperative pain control, resulting in less opioids side effects, promoting recovery and faster home readiness. Spinal alpha2 agonist drugs are not used routinely as a single analgesic in the postoperative period. A single dose of spinal clonidine as a sole postoperative analgesic has poor effect. When clonidine is added to spinal local anaesthetics or spinal opioids it does extend the time to first analgesic dose and decrease the total amount of systemic postoperative opioids. Clonidine spinal synergism with other analgesics is due to antinoci‐ ceptive actions that have been described in previous paragraphs. In previous sections we have discussed some aspects of postoperative analgesia produced by intrathecal clonidine in various surgical scenarios. In this section we discuss more details on the prevention of

Adding clonidine 150 µg to spinal bupivacaine in patients undergoing femoral osteosynthesis prolonged significantly the first request for analgesics compared to oral clonidine and plain spinal bupivacaine (337±29 min, 313±29 versus 236±27 min respectively), and reduced the total dose of morphine. [96] Combining 50 mg of hyperbaric lidocaine, 25 µg fentanyl, and clonidine 150 µg produced excellent postoperative analgesia in proctological patients. [97] Small doses of spinal clonidine also produce postoperative analgesia without deleterious side effects. In a comparative evaluation of 15 µg versus 30 µg clonidine as analgesic adjuvant added to 15 mg of spinal 0.5% hyperbaric bupivacaine in 90 patients undergoing abdominal hysterectomy, the authors [98] found a prolonged first pain complaint time for those women treated with clonidine compared with patients who did not received spinal clonidine (315.37+50.3, 387.07+83.19 versus 204.8+34.8 minutes). Hemodynamic parameters were alike in all patients. A recent meta-analysis by Engelman and Marsala [99] found that clonidine increased the duration of postoperative analgesia by 1.63 h [95% confidence interval (CI): 0.93-2.33]. There was a 90% probability that clonidine increases the duration of postoperative analgesia by more than 75 min compared with morphine alone. They also found that spinal clonidine decrease the need for postoperative morphine by a mean of 4.45 mg. (95% CI: 1.40-7.49 mg). Hypoten‐ sion was the only side effect increased by clonidine (odds ratio 1.78; 95% CI: 1.02-3.12). In patients undergoing transurethral surgery, 25 µg clonidine plus 7.5 mg of subarachnoid isobaric bupivacaine significantly delayed time for first request supplemental analgesia compared to bupivacaine alone (434.1±78. 3 min versus 263.97±40.38 min p=0.000) respectively. [48] In a recent study done with clonidine 30 µg added to intratecal bupivacaine-fentanyl, the authors demonstrated that the incidence of intraoperative pain and postoperative analgesic requirements were significantly less compared with the patient who did not received the alfa2

Chest pain after coronary artery bypass surgery has been relieved with intrathecal clonidine in doses 1 µg/kg or 100 µg, with or without spinal opioids. Adding clonidine to neuraxial opioids improves the quality of analgesia postoperatively and expedites the process of weaning from mechanical ventilation, allowing earlier extubation. No serious side effects have

Baker and coworkers [104] hypothesized that hyperbaric clonidine avoid its rostral migration, and consequently reduced some of its side effects such as hypotension, bradycardia and sedation. They use 150 µg of either isobaric or hyperbaric clonidine in 30 elderly patients found

postoperative pain with spinal clonidine.

110 Topics in Spinal Anaesthesia

agonist for vaginal hysterectomy. [100]

been described. [101, 102, 103]

As reviewed, there is no universal agreement on recommended dose for the various clinical uses of spinal clonidine. Recently, Ginosar, Riley and Angst [105] did a nice study in volunteers and found out a clonidine dose dependant effect. Significant analgesia to experimental heat pain was detected above 25 µg. After 50 µg the heat pain tolerance increased by that ∼1°C, similar to the analgesic effect of 5 mg epidural morphine or 30 µg epidural fentanyl observed in studies using this experimental heat pain model.

Table 1 shows the different doses of intrathecal clonidine in different clinical scenarios of subarachnoid anaesthesia and analgesia. It can be seen that the dose range is wide as already discussed in this chapter. Up until today, there is not a standard recommended dose of subarachnoid clonidine. Doses range from 15 up to 450µg. It is necessary to adjust the dose to several factors: age, type of patients, time of surgery, type of surgery and dose of local anaesthetic and intrathecal opioids used.

for intrathecal use has motivated innumerable research due to its ability to improve anaes‐ thesia and neuraxial analgesia without the side effects of opioids such as respiratory depres‐ sion, pruritus and urinary retention. Their analgesic effect is due to their binding on alpha2 adrenoreceptors localized in the brainstem nuclei and spinal substantia gelatinosa linked to analgesic mechanisms. A synergistic action between opioids and clonidine at the level of the spinal cord has been suggested. Clonidine also acts synergistically with local anaesthetics because of its action of opening potassium channels. Side effects of intrathecal clonidine include sedation, hypotension and a reduction of the heart rate. Spinal clonidine doses from 15 up to 450 µg are used in diverse clinical scenarios as adjuvant drug to local anaesthetics and/or opioids with the main goal to enhance spinal analgesia-anaesthesia. Clonidine and dexmedetomidine side effects are sedation, dose related bradycardia and hypotension, but rarely reach critical levels and are easy to treat. The largest evidence about the effectiveness of intrathecal clonidine is provided by studies on post-surgical pain. Although intratecal clonidine is safe, in obstetrics patients we still need to use the smallest dose based on current

Intrathecal Clonidine as Spinal Anaesthesia Adjuvant — Is there a Magical Dose?

http://dx.doi.org/10.5772/58712

113

This chapter may serve as a review to help clinicians decide whether or not to use spinal

1 Anaesthesiology, Pain Medicine, Internal Medicine and Critical Care Medicine, Hospital

2 Anaesthesiology and Critical Care Medicine, Instituto Mexicano del Seguro Social and

[1] Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an

[2] Bloor B. Clonidine and other alpha2 adrenergic agonists: and important new drug

[3] Eisenach JC, De Kock M, Klimscha W.alpha(2)-adrenergic agonists for regional anes‐ thesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996;85:655-74.

General de Tijuana, ISESALUD and Centro Médico del Noroeste, Tijuana , México

and Susana Preciado-Ramírez3

, Juan C. Flores-Carrillo2

3 Anaesthesiology Fundación Médica Sur, México D.F., México

alpha-adrenergic agonist. Anesth Analg 1982;61:741-5.

class for the perioperative period. Sem Anesth 1988;7:170-77.

recommendations.

**Author details**

**References**

Víctor M. Whizar-Lugo1

clonidine as adjuvant drugs in their daily practice.

Centro Médico del Noroeste, Tijuana, México

**Table 1.** Use of spinal clonidine

#### **15. Conclusions**

Spinal anaesthesia was described over 100 years ago. Since then, neuroaxial drug administra‐ tion has advanced exponentially and nowadays includes a large variety of medication that provides not only anaesthesia, but analgesia as well. The growing interest in alpha2 agonists for intrathecal use has motivated innumerable research due to its ability to improve anaes‐ thesia and neuraxial analgesia without the side effects of opioids such as respiratory depres‐ sion, pruritus and urinary retention. Their analgesic effect is due to their binding on alpha2 adrenoreceptors localized in the brainstem nuclei and spinal substantia gelatinosa linked to analgesic mechanisms. A synergistic action between opioids and clonidine at the level of the spinal cord has been suggested. Clonidine also acts synergistically with local anaesthetics because of its action of opening potassium channels. Side effects of intrathecal clonidine include sedation, hypotension and a reduction of the heart rate. Spinal clonidine doses from 15 up to 450 µg are used in diverse clinical scenarios as adjuvant drug to local anaesthetics and/or opioids with the main goal to enhance spinal analgesia-anaesthesia. Clonidine and dexmedetomidine side effects are sedation, dose related bradycardia and hypotension, but rarely reach critical levels and are easy to treat. The largest evidence about the effectiveness of intrathecal clonidine is provided by studies on post-surgical pain. Although intratecal clonidine is safe, in obstetrics patients we still need to use the smallest dose based on current recommendations.

This chapter may serve as a review to help clinicians decide whether or not to use spinal clonidine as adjuvant drugs in their daily practice.

#### **Author details**

**Type of surgery Dose range µg Effects Reported side effects References**

Enhance quality anaesthesia Prolongs time to void

76] 50 to 200\* Reduce labour pain Maternal dry mouth

Prolongs analgesia Fetal acidosis

Cesarean 37.5 to 450 Enhance anaesthesia Maternal hypotension [81, 82, 83,

Pediatrics 1 to 2 \*\* Prolongs spinal blockage Sedation \*\*\* [92, 93, 94,

95] Reduces propofol dose Hypotension\*\*\*

30 to 450 Enhance spinal anaesthesia Sedation [48, 96, 97,

Prolongs time for first analgesic

Prolongs time for first analgesic

Prolongs postoperative analgesia in a dose response manner

Decrease postoperative opioids

Spinal anaesthesia was described over 100 years ago. Since then, neuroaxial drug administra‐ tion has advanced exponentially and nowadays includes a large variety of medication that provides not only anaesthesia, but analgesia as well. The growing interest in alpha2 agonists

Postoperative analgesia Sedation

Facilitates high spinal block [37, 53, 54,

Maternal hypotension [69, 70, 71,

Fetal arrhythmias

Respiratory depression\*\*\*

Dose below 150 µg may induce more hypotension

Bradycardia

55, 56, 57, 58, 60, 61]

72, 73, 74, 75,

84, 85, 86, 87,

98, 99, 100, 102, 103]

88]

Longer postoperative analgesia Reduce intraoperative opioids

segment and motor block

Prolongs time for first analgesic

duration

analgesia

request

request

doses

\* Sole analgesic, \*\* µg/kg, \*\*\* Only with 2 µg/kg

**Table 1.** Use of spinal clonidine

**15. Conclusions**

Orthopaedics 15 to 150 Increases regression to L1

Labour analgesia 15 to 45 Potentiates opioid spinal

1-2 µg/kg

Obstetrics

112 Topics in Spinal Anaesthesia

Post operative analgesia

Víctor M. Whizar-Lugo1 , Juan C. Flores-Carrillo2 and Susana Preciado-Ramírez3

1 Anaesthesiology, Pain Medicine, Internal Medicine and Critical Care Medicine, Hospital General de Tijuana, ISESALUD and Centro Médico del Noroeste, Tijuana , México

2 Anaesthesiology and Critical Care Medicine, Instituto Mexicano del Seguro Social and Centro Médico del Noroeste, Tijuana, México

3 Anaesthesiology Fundación Médica Sur, México D.F., México

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[60] Gehling M, Tryba M, Lüsebrink T, Zorn A. Can the addition of clonidine improve the analgesic efficacy of low dose intrathecal morphine? A randomised double-blind tri‐

[61] Grace D, Milligan KR, Morrow BJ, Fee JP. Co-administration of pethidine and cloni‐ dine: a spinal anaesthetic technique for total hip replacement. Br J Anaesth

[62] Hong RW. Less is more: the recent history of neuraxial labor analgesia. Am J Ther.

[63] Roelants F. The use of neuraxial adjuvant drugs (neostigmine, clonidine) in obstet‐

[64] Datta S. Spinal opiates in obstetrics. In Obstetric anaesthesia handbook. Fourth Edi‐

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[66] Sultan P, Murphy C, Halpern S, Carvalho B. The effect of low concentrations versus high concentrations of local anesthetics for labour analgesia on obstetric and anes‐

[68] Van de Velde M. Neuraxial analgesia and fetal bradycardia. Curr Opin Anaesthesiol

[69] Mercier FJ, Boulay G, Ben Ayed M, Benhamou D.Combined spinal and epidural an‐ algesia for labor. Prolongation by addition of a minidose of clonidine to sufentanil.

[70] Mercier FJ, Dounas M, Bouaziz H, Des Mesnards-Smaja V, Foiret C, Vestermann MN, Fischler M, Benhamou D. The effect of adding a minidose of clonidine to intra‐

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[96] Dobrydnjov I, Axelsson K, Samarütel J, Holmström B.Postoperative pain relief fol‐ lowing intrathecal bupivacaine combined with intrathecal or oral clonidine. Acta An‐

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[99] Engelman E, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute

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7 pages.

120 Topics in Spinal Anaesthesia

**Chapter 6**

**Midazolam in Spinal Anesthesia — Intrathecal or**

The first spinal anesthesia was carried out by Dr August Bier in 1899 and his anesthetic technique has become the standard practice for lower extremity and abdominal surgery worldwide [1]. Nowadays, the most commonly used drugs for spinal anesthesia are local anesthetics. However, a major disadvantage of single injection spinal anesthesia is its limited duration of action. In clinical practice, a number of adjuvants have been added to intrathecal local anesthetics for supplementation of intraoperative anesthesia and postoperative analge‐ sia. They have advantages as they reduce the dose of local anesthetic; provide long lasting postoperative analgesia with reduced incidence of central nervous system depression, motor

Midazolam, synthesized by Walsar and colleagues in 1976, was the first clinically used water soluble benzodiazepine [3]. It is also the first benzodiazepine that was produced primarily for use in anesthesia [4]. In 1986, Faull and Villiger demonstrated that there is a high density of benzodiazepine (*GABA*‐*A*) receptors in lamina II of the dorsal horn in the human spinal cord, suggesting a possible role in pain modulation [5]. One year later, Goodchild and Serrao reported that benzodiazepines might have analgesic effects at the spinal cord level in animals [6]. In 1990s, analgesic efficacy of intrathecal midazolam in humans has been demonstrated [7-9]. Naltrindole, a δ-selective opioid antagonistic agent, suppresses the antinociceptive effect of intrathecal midazolam, suggesting that intrathecal midazolam is involved in the release of

This chapter is going to focus on the relationship between midazolam and spinal anesthesia.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Intravenous?**

Beyazit Zencirci

**1. Introduction**

effects or hypotension [2].

http://dx.doi.org/10.5772/58750

Additional information is available at the end of the chapter

an endogenous opioid acting at spinal δ receptors [10].

## **Midazolam in Spinal Anesthesia — Intrathecal or Intravenous?**

Beyazit Zencirci

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58750

#### **1. Introduction**

The first spinal anesthesia was carried out by Dr August Bier in 1899 and his anesthetic technique has become the standard practice for lower extremity and abdominal surgery worldwide [1]. Nowadays, the most commonly used drugs for spinal anesthesia are local anesthetics. However, a major disadvantage of single injection spinal anesthesia is its limited duration of action. In clinical practice, a number of adjuvants have been added to intrathecal local anesthetics for supplementation of intraoperative anesthesia and postoperative analge‐ sia. They have advantages as they reduce the dose of local anesthetic; provide long lasting postoperative analgesia with reduced incidence of central nervous system depression, motor effects or hypotension [2].

Midazolam, synthesized by Walsar and colleagues in 1976, was the first clinically used water soluble benzodiazepine [3]. It is also the first benzodiazepine that was produced primarily for use in anesthesia [4]. In 1986, Faull and Villiger demonstrated that there is a high density of benzodiazepine (*GABA*‐*A*) receptors in lamina II of the dorsal horn in the human spinal cord, suggesting a possible role in pain modulation [5]. One year later, Goodchild and Serrao reported that benzodiazepines might have analgesic effects at the spinal cord level in animals [6]. In 1990s, analgesic efficacy of intrathecal midazolam in humans has been demonstrated [7-9]. Naltrindole, a δ-selective opioid antagonistic agent, suppresses the antinociceptive effect of intrathecal midazolam, suggesting that intrathecal midazolam is involved in the release of an endogenous opioid acting at spinal δ receptors [10].

This chapter is going to focus on the relationship between midazolam and spinal anesthesia.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. Midazolam**

Benzodiazepines commonly used in the perioperative period include diazepam, midazolam, and lorazepam, as well as the selective benzodiazepine antagonist flumazenil (Figure 1). The chemical structure of the benzodiazepines contains a benzene ring fused to a seven-member diazepine ring, hence their name. They are all composed of a benzene ring (*A*) fused to a sevenmembered 1, 4-diazepine ring (*B*). Anesthesiologically relevant benzodiazepine agonists also contain a 5-aryl substituent (*ring C*), which enhances the pharmacological potency. However, the benzodiazepine antagonist flumazenil has two important structural differences as com‐ pared to the above agonists. Flumazenil has a keto function at position 5 instead of ring C, and a methyl substituent at position 4. Hence benzodiazepines are unique among the group of intravenous anesthetics in that their action can readily be terminated by administration of their selective antagonist flumazenil [11, 12].

is 6-15 min [17]. The fused imidazole ring of midazolam is oxidized much more rapidly than the methylene group of the diazepine ring of other benzodiazepines [18-20]. In elderly men, the clearance of midazolam is reduced and the elimination half-time is prolonged as compared to young males. Between elderly and young women, however, no significant differences were detected in the clearance or the elimination halftime of midazolam [15]. In addition to the liver, midazolam is also metabolized at extrahepatic sites. This has been demonstrated by the discovery of metabolites following intravenous injection of midazolam during the anhepatic period of liver transplantation [21]. In patients with advanced cirrhosis of the liver, the plasma clearance is reduced and the elimination half-time is prolonged as compared to healthy

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125

The first step in the metabolism of midazolam is hydroxylation [23]. The two metabolites formed are α-hydroxymidazolam and 4-hydroxymidazolam, both are pharmacologically active [14, 24]. The α-hydroxymidazolam is as potent as the parent compound and may contribute significantly to the effects of the parent drug when present in sufficiently high concentrations. 4-Hydroxymidazolam is quantitatively unimportant [25]. Both metabolites are rapidly conjugated by glucuronic acid to form products which have been considered to be pharmacologically inactive [14]. On the other hand; glucuronidated α-hydroxymidazolam, the main metabolite of midazolam, has a substantial pharmacological effect and can penetrate the intact blood–brain barrier. The elimination half-time of α-hydroxymidazolam is about 70 min [25]. However, it can accumulate in patients with renal failure. Furthermore, in vitro binding studies show that the affinity of glucuronidated α-hydroxymidazolam to the cerebral benzo‐ diazepine receptor is only about ten times weaker than that of midazolam or unconjugated

Midazolam is supplied as hydrochloride salt with a pH less than 4.0 (*buffered to an acidic pH of 3.5*). This is important because midazolam displays pH-dependent solubility. The diazepine ring of midazolam accounts for its stability in solution and rapid metabolism. It remains open at pH value of <4, thus maintaining drug´s water solubility. The ring closes at pH value of > 4, as when the drug is exposed to physiologic pH, thus converting midazolam to a highly lipid soluble drug [27] and this lipophilicity is responsible for its rapid CNS effect and large volume of distribution [28]. Therefore the pH of the commercial midazolam hydrochloride preparation is adjusted to 3 with hydrochloride acid and sodium hydroxide. As midazolam is injected into

Midazolam exerts its effect by occupying benzodiazepine receptor that modulates γ-amino butyric acid (*GABA*), the major inhibitory neurotransmitter in the brain. Benzodiazepine receptors are found in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, inferior colliculus, brain stem, and spinal cord. There are two types of GABA receptors; benzodiazepine receptors are part of the benzodiazepine-GABAA-chloride channel receptor complex. Benzodiazepine binding site is located on the γ2 subunit of the GABA receptor complex [29, 30]. With the activation of the GABAA receptor, gating of the channel for chloride ions is started after which the cell becomes hyperpolarised and resistant to neuronal excitation. The hypnotic effects of benzodiazepine are mediated by alterations in the potential dependent calcium ion flux [31]. Hypnotic, sedative, amnesic, and anticonvulsant effects are mediated by

patients, pH is increased and the ring is closed thus increasing the lipid solubility.

volunteers, while the volume of distribution remains unchanged [22].

α-hydroxymidazolam [26].

**Figure 1.** Chemical structure of the three commonly used benzodiazepines and their antogonist flumazenil.

Midazolam is an imidazobenzodiazepine. This results in the ability of a water molecule to open the diazepine ring, thus encouraging aqueous solubility. The equilibrium between the two forms of midazolam is determined by pH. The change from one form to the other is relatively slow, having a half-life of 10 minutes. The pH in the ampoule containing midazolam hydro‐ chloride is 3.0 and so the ring is open and it is soluble. Once subjected to body pH 7.4, the diazepine ring closes and the midazolam becomes lipid-soluble, allowing it readily to cross the blood–brain barrier. In the plasma most of the midazolam (*95%*) is protein-bound. Small changes in its plasma protein binding will produce large changes in the amount of free drug available, which may have consequences in clinical practice [13]. The high lipophilicity of midazolam accounts for the relatively large volume of distribution at steady-state [14]. Older age does not increase the volume of distribution significantly [15, 16]. However, in obese patients, the volume of distribution is increased and the elimination half-time is prolonged while the clearance remains unchanged [15].

Elimination half-time is independent of the route of administration. Major operations seem to increase the volume of distribution and prolong the elimination half-time [16]. Following intravenous administration, midazolam is rapidly distributed and the distribution half-time is 6-15 min [17]. The fused imidazole ring of midazolam is oxidized much more rapidly than the methylene group of the diazepine ring of other benzodiazepines [18-20]. In elderly men, the clearance of midazolam is reduced and the elimination half-time is prolonged as compared to young males. Between elderly and young women, however, no significant differences were detected in the clearance or the elimination halftime of midazolam [15]. In addition to the liver, midazolam is also metabolized at extrahepatic sites. This has been demonstrated by the discovery of metabolites following intravenous injection of midazolam during the anhepatic period of liver transplantation [21]. In patients with advanced cirrhosis of the liver, the plasma clearance is reduced and the elimination half-time is prolonged as compared to healthy volunteers, while the volume of distribution remains unchanged [22].

**2. Midazolam**

124 Topics in Spinal Anaesthesia

selective antagonist flumazenil [11, 12].

while the clearance remains unchanged [15].

Benzodiazepines commonly used in the perioperative period include diazepam, midazolam, and lorazepam, as well as the selective benzodiazepine antagonist flumazenil (Figure 1). The chemical structure of the benzodiazepines contains a benzene ring fused to a seven-member diazepine ring, hence their name. They are all composed of a benzene ring (*A*) fused to a sevenmembered 1, 4-diazepine ring (*B*). Anesthesiologically relevant benzodiazepine agonists also contain a 5-aryl substituent (*ring C*), which enhances the pharmacological potency. However, the benzodiazepine antagonist flumazenil has two important structural differences as com‐ pared to the above agonists. Flumazenil has a keto function at position 5 instead of ring C, and a methyl substituent at position 4. Hence benzodiazepines are unique among the group of intravenous anesthetics in that their action can readily be terminated by administration of their

**Figure 1.** Chemical structure of the three commonly used benzodiazepines and their antogonist flumazenil.

Midazolam is an imidazobenzodiazepine. This results in the ability of a water molecule to open the diazepine ring, thus encouraging aqueous solubility. The equilibrium between the two forms of midazolam is determined by pH. The change from one form to the other is relatively slow, having a half-life of 10 minutes. The pH in the ampoule containing midazolam hydro‐ chloride is 3.0 and so the ring is open and it is soluble. Once subjected to body pH 7.4, the diazepine ring closes and the midazolam becomes lipid-soluble, allowing it readily to cross the blood–brain barrier. In the plasma most of the midazolam (*95%*) is protein-bound. Small changes in its plasma protein binding will produce large changes in the amount of free drug available, which may have consequences in clinical practice [13]. The high lipophilicity of midazolam accounts for the relatively large volume of distribution at steady-state [14]. Older age does not increase the volume of distribution significantly [15, 16]. However, in obese patients, the volume of distribution is increased and the elimination half-time is prolonged

Elimination half-time is independent of the route of administration. Major operations seem to increase the volume of distribution and prolong the elimination half-time [16]. Following intravenous administration, midazolam is rapidly distributed and the distribution half-time The first step in the metabolism of midazolam is hydroxylation [23]. The two metabolites formed are α-hydroxymidazolam and 4-hydroxymidazolam, both are pharmacologically active [14, 24]. The α-hydroxymidazolam is as potent as the parent compound and may contribute significantly to the effects of the parent drug when present in sufficiently high concentrations. 4-Hydroxymidazolam is quantitatively unimportant [25]. Both metabolites are rapidly conjugated by glucuronic acid to form products which have been considered to be pharmacologically inactive [14]. On the other hand; glucuronidated α-hydroxymidazolam, the main metabolite of midazolam, has a substantial pharmacological effect and can penetrate the intact blood–brain barrier. The elimination half-time of α-hydroxymidazolam is about 70 min [25]. However, it can accumulate in patients with renal failure. Furthermore, in vitro binding studies show that the affinity of glucuronidated α-hydroxymidazolam to the cerebral benzo‐ diazepine receptor is only about ten times weaker than that of midazolam or unconjugated α-hydroxymidazolam [26].

Midazolam is supplied as hydrochloride salt with a pH less than 4.0 (*buffered to an acidic pH of 3.5*). This is important because midazolam displays pH-dependent solubility. The diazepine ring of midazolam accounts for its stability in solution and rapid metabolism. It remains open at pH value of <4, thus maintaining drug´s water solubility. The ring closes at pH value of > 4, as when the drug is exposed to physiologic pH, thus converting midazolam to a highly lipid soluble drug [27] and this lipophilicity is responsible for its rapid CNS effect and large volume of distribution [28]. Therefore the pH of the commercial midazolam hydrochloride preparation is adjusted to 3 with hydrochloride acid and sodium hydroxide. As midazolam is injected into patients, pH is increased and the ring is closed thus increasing the lipid solubility.

Midazolam exerts its effect by occupying benzodiazepine receptor that modulates γ-amino butyric acid (*GABA*), the major inhibitory neurotransmitter in the brain. Benzodiazepine receptors are found in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, inferior colliculus, brain stem, and spinal cord. There are two types of GABA receptors; benzodiazepine receptors are part of the benzodiazepine-GABAA-chloride channel receptor complex. Benzodiazepine binding site is located on the γ2 subunit of the GABA receptor complex [29, 30]. With the activation of the GABAA receptor, gating of the channel for chloride ions is started after which the cell becomes hyperpolarised and resistant to neuronal excitation. The hypnotic effects of benzodiazepine are mediated by alterations in the potential dependent calcium ion flux [31]. Hypnotic, sedative, amnesic, and anticonvulsant effects are mediated by α1 GABA receptors and anxiolysis and centrally acting muscle relexant properties are mediated by α2 GABA receptors [31].

Intrathecal midazolam was originally shown to have antinociceptive properties in animals in the early 1980s [41, 42]. And later in 1991, Malinovsky et al. demonstrated potential of neurotoxic effect of intrathecal administration of ketamine and midazolam in rabbits [43]. Midazolam-treated rabbits showed significant changes in both blood-brain barrier and light microscopy studies. They postulated that, the neurotoxicity might be due to the 10% HCL used as a vehicle in the preparation of midazolam. In 1999 Erdine et al. conducted a study of intrathecal midazolam in rabbits and reported neurotoxicity [44]. They concluded that the neurotoxicity was due to the use of intrathecal catheter. They also reported that this toxic change did not produce any change in the vital parameters of those animals. However, in 1991 Schoeffler et al. conducted a detailed histological study in rats following administration of midazolam via subarachnoid catheter while investigating control of cancer pain [45]. They found that the amount of fibrosis, infiltration, and deformation in midazolam group is not different from saline control group. Aguilar et al. in 1994, conducted study and reported that intrathecal midazolam can relieve pain in different clinical situations (*as long as 13 months*) and they did not show any toxic neurological effects following prolonged administration of intrathecal midazolam [46]. Nevetheless, in 1995 Svensson et al. conducted a morphological study on rat spinal cords following chronic subarachnoid administration of midazolam,

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In 1996, Valentine et al. studied the effect of intrathecal midazolam along with hyperbaric bupivacaine for caesarean section delivery under spinal anaesthesia and found no side effects attributable to midazolam [8]. In the same year, Borg and Krijnen reported long-term intra‐ thecal administration of midazolam and clonidine in patients with refractory musculoskeletal pain persisting more than 2.5 years [9]. They administered intrathecal midazolam up to 6mg/ day which showed promising results, they also reported that this high dose did not cause any neurological deficits in those patients suffering with chronic refractory musculoskeletal pain [9]. One year later, Bozkurt et al. studied the histological change following epidural adminis‐ tration of midazolam in neonatal rabbits and showed a variable degree of neurotoxic effects such as degeneration of vacuoles, cytoplasm and neurofilaments, disruption of myelin sheaths, lysis of cell membranes, perivascular oedema, and pyknosis of nuclei [48]. The toxic effects of acidic saline and midazolam (*commercially available preparations*) were similar. In the same year, Bahar et al. examined in an animal model whether intrathecal midazolam, alone or with fentanyl, can achieve anaesthesia sufficient for laparotomy, comparable to lidocaine; they concluded that midazolam, when injected intrathecally, produces reversible, segmental, spinally mediated antinociception, sufficient to provide balanced anaesthesia without any adverse effect [49]. In 1999, Nishiyama et al. conducted histopathological study in cats with intrathecal midazolam. Neither acute histological damage nor inflammatory reaction of the

In 1998, Nishiyama et al. studied the effect of continuous infusion of midazolam with local anesthetic for treatment of postoperative pain and showed that adding midazolam to a continuous epidural infusion of bupivacaine provides better analgesia, amnesia, and sedation than bupivacaine alone without any side effects [51]. Also Nishiyama et al. in the same year studied the effect of adding midazolam and bupivacaine to human cerebrospinal fluid in glass

documenting its neurotoxic effect [47].

spinal cord were seen in the cats [50].

The anxiolytic effect of midazolam is via its action at mammillary body. Presumably midazolam exerts its anxiolytic property like other benzodiazepines by increasing glycine inhibitory neurotransmitter. Midazolam also possesses anticonvulsant action which is attributed to enhanced activity of GABA on the brain's motor circuit. It exhibits a muscle relaxant effect via its action at the glycine receptors in the spinal cord. Midazolam administered via intrathecal or epidural routes can produce analgesia, probably due to its GABA mediated action [4]. Other mechanisms of action including its interaction with opiate receptors have also been proposed [10].

#### **3. Intrathecal midazolam: Useful or toxic?**

Spinal anesthesia is the most commonly used regional anesthetic technique. Local anesthetic agents used for this purpose provide good intraoperative analgesia. However, they provide a very limited postoperative duration of action. In order to overcome this problem and to maximise the duration of anesthesia-analgesia, many adjuvants, such as intrathecal opioids and non-opioids, have increasingly been tried in the last two decades to relieve postoperative pain [32-34]. Among the various methods availabe for providing post-operative analgesia, the benefits of intrathecal opioids and non-opioids as adjuncts in spinal anaesthesia are well documented. Unfortunately the addition of intrathecal opioids is associated with dose-related adverse effects such as respiratory depression, nausea, vomiting, urinary retention, pruritus, and sedation [35]. Therefore, the use of non-opioids such as ketamine, clonidine, neostigmine, magnesium sulfate, and midazolam have become popular adjuncts for post-operative analgesia. However, side-effects in the postoperative period render most adjuvants less than ideal.

Midazolam, a water soluble benzodiazepine, has been used via intrathecal route in the management of acute (*perioperative*) [36, 37], chronic [38] and cancer [39] pain. Goodchild and Noble were the first to demonstrate the role of intrathecal midazolam in relieving pain of somatic origin in humans [36]. The rationale for the use of intrathecal midazolam focuses on the awareness that it is an agonist at the benzodiazepine binding site, a subunit of the pen‐ tameric gammaaminobutyric acid (*GABA-A*) receptor. Agonist occupancy of the benzodiaze‐ pine binding site enhances the activity of GABA at the GABA-A receptor. The GABA receptor is a chloride ionophore that, when activated, typically stabilises the transmembrane potential at, or near, the resting potential. In neurons, this typically serves to decrease excitability [40]. Intrathecal benzodiazepine-induced analgesia is spinally mediated. Binding sites are GABA receptors, abundantly present in the dorsal root nerve cells, with the maximum concentration found within lamina II of the dorsal nerve cells, a region that plays a prominent role in processing nociceptive and thermoceptive stimulation [36]. The present cumulative experience with intrathecal midazolam across species broadly confirms the safety thereof, the analgesic activity of the molecule and its benzodiazepine pharmacology, and the lack of irreversible effects [8].

Intrathecal midazolam was originally shown to have antinociceptive properties in animals in the early 1980s [41, 42]. And later in 1991, Malinovsky et al. demonstrated potential of neurotoxic effect of intrathecal administration of ketamine and midazolam in rabbits [43]. Midazolam-treated rabbits showed significant changes in both blood-brain barrier and light microscopy studies. They postulated that, the neurotoxicity might be due to the 10% HCL used as a vehicle in the preparation of midazolam. In 1999 Erdine et al. conducted a study of intrathecal midazolam in rabbits and reported neurotoxicity [44]. They concluded that the neurotoxicity was due to the use of intrathecal catheter. They also reported that this toxic change did not produce any change in the vital parameters of those animals. However, in 1991 Schoeffler et al. conducted a detailed histological study in rats following administration of midazolam via subarachnoid catheter while investigating control of cancer pain [45]. They found that the amount of fibrosis, infiltration, and deformation in midazolam group is not different from saline control group. Aguilar et al. in 1994, conducted study and reported that intrathecal midazolam can relieve pain in different clinical situations (*as long as 13 months*) and they did not show any toxic neurological effects following prolonged administration of intrathecal midazolam [46]. Nevetheless, in 1995 Svensson et al. conducted a morphological study on rat spinal cords following chronic subarachnoid administration of midazolam, documenting its neurotoxic effect [47].

α1 GABA receptors and anxiolysis and centrally acting muscle relexant properties are

The anxiolytic effect of midazolam is via its action at mammillary body. Presumably midazolam exerts its anxiolytic property like other benzodiazepines by increasing glycine inhibitory neurotransmitter. Midazolam also possesses anticonvulsant action which is attributed to enhanced activity of GABA on the brain's motor circuit. It exhibits a muscle relaxant effect via its action at the glycine receptors in the spinal cord. Midazolam administered via intrathecal or epidural routes can produce analgesia, probably due to its GABA mediated action [4]. Other mechanisms of action including its interaction with opiate

Spinal anesthesia is the most commonly used regional anesthetic technique. Local anesthetic agents used for this purpose provide good intraoperative analgesia. However, they provide a very limited postoperative duration of action. In order to overcome this problem and to maximise the duration of anesthesia-analgesia, many adjuvants, such as intrathecal opioids and non-opioids, have increasingly been tried in the last two decades to relieve postoperative pain [32-34]. Among the various methods availabe for providing post-operative analgesia, the benefits of intrathecal opioids and non-opioids as adjuncts in spinal anaesthesia are well documented. Unfortunately the addition of intrathecal opioids is associated with dose-related adverse effects such as respiratory depression, nausea, vomiting, urinary retention, pruritus, and sedation [35]. Therefore, the use of non-opioids such as ketamine, clonidine, neostigmine, magnesium sulfate, and midazolam have become popular adjuncts for post-operative analgesia. However, side-effects in the postoperative period render most adjuvants less than

Midazolam, a water soluble benzodiazepine, has been used via intrathecal route in the management of acute (*perioperative*) [36, 37], chronic [38] and cancer [39] pain. Goodchild and Noble were the first to demonstrate the role of intrathecal midazolam in relieving pain of somatic origin in humans [36]. The rationale for the use of intrathecal midazolam focuses on the awareness that it is an agonist at the benzodiazepine binding site, a subunit of the pen‐ tameric gammaaminobutyric acid (*GABA-A*) receptor. Agonist occupancy of the benzodiaze‐ pine binding site enhances the activity of GABA at the GABA-A receptor. The GABA receptor is a chloride ionophore that, when activated, typically stabilises the transmembrane potential at, or near, the resting potential. In neurons, this typically serves to decrease excitability [40]. Intrathecal benzodiazepine-induced analgesia is spinally mediated. Binding sites are GABA receptors, abundantly present in the dorsal root nerve cells, with the maximum concentration found within lamina II of the dorsal nerve cells, a region that plays a prominent role in processing nociceptive and thermoceptive stimulation [36]. The present cumulative experience with intrathecal midazolam across species broadly confirms the safety thereof, the analgesic activity of the molecule and its benzodiazepine pharmacology, and the lack of irreversible

mediated by α2 GABA receptors [31].

126 Topics in Spinal Anaesthesia

receptors have also been proposed [10].

ideal.

effects [8].

**3. Intrathecal midazolam: Useful or toxic?**

In 1996, Valentine et al. studied the effect of intrathecal midazolam along with hyperbaric bupivacaine for caesarean section delivery under spinal anaesthesia and found no side effects attributable to midazolam [8]. In the same year, Borg and Krijnen reported long-term intra‐ thecal administration of midazolam and clonidine in patients with refractory musculoskeletal pain persisting more than 2.5 years [9]. They administered intrathecal midazolam up to 6mg/ day which showed promising results, they also reported that this high dose did not cause any neurological deficits in those patients suffering with chronic refractory musculoskeletal pain [9]. One year later, Bozkurt et al. studied the histological change following epidural adminis‐ tration of midazolam in neonatal rabbits and showed a variable degree of neurotoxic effects such as degeneration of vacuoles, cytoplasm and neurofilaments, disruption of myelin sheaths, lysis of cell membranes, perivascular oedema, and pyknosis of nuclei [48]. The toxic effects of acidic saline and midazolam (*commercially available preparations*) were similar. In the same year, Bahar et al. examined in an animal model whether intrathecal midazolam, alone or with fentanyl, can achieve anaesthesia sufficient for laparotomy, comparable to lidocaine; they concluded that midazolam, when injected intrathecally, produces reversible, segmental, spinally mediated antinociception, sufficient to provide balanced anaesthesia without any adverse effect [49]. In 1999, Nishiyama et al. conducted histopathological study in cats with intrathecal midazolam. Neither acute histological damage nor inflammatory reaction of the spinal cord were seen in the cats [50].

In 1998, Nishiyama et al. studied the effect of continuous infusion of midazolam with local anesthetic for treatment of postoperative pain and showed that adding midazolam to a continuous epidural infusion of bupivacaine provides better analgesia, amnesia, and sedation than bupivacaine alone without any side effects [51]. Also Nishiyama et al. in the same year studied the effect of adding midazolam and bupivacaine to human cerebrospinal fluid in glass test tubes and the solution was examined for any change of pH and a reduction in the transparency of the solution [52]. Cerebrospinal pH was decreased to below 7.0 adding more than 3 mg of midazolam, more than 1.9 mL of 0.25% bupivacaine or 1.3 mL of the mixture. Cerebrospinal transparency by adding more than 0.7 mg of midazolam, 1.1 mL of 0.25% bupivacaine or 0.6 mL of the mixture. Midazolam in saline neither decreased the pH below nor reduced transparency. These results are very important so this study showed that clinically useful doses of intrathecal or epidural midazolam were not neurotoxic. In the same year, Gulec et al. showed that caudal administration of a bupivacaine-midazolam mixture produces a longer duration of postoperative analgesia than a bupivacaine-morphine mixture and bupivacaine alone [53]. Batra et al. in 1999, conducted a study on postoperative analgesia in patients undergoing knee arthroscopy following intrathecal administration of midazolam in combination with hyperbaric bupivacaine [54]. They demonstrated that this combination produces better postoperative analgesia. In 2001, Kim and Lee showed a dose-dependent effect of intrathecal midazolam [55]. Sen et al. reported that intrathecal midazolam produced significant postoperative pain relief together with antiemetic effect and tranquillity in patients undergoing caesarean section delivery [56]. Maharjan et al showed that caudal administration of midazolam-bupivacaine mixture significantly prolongs postoperative analgesia compared to bupivacaine alone in children undergoing genitourinary surgery [57]. Moreover, other studies have shown that addition of intrathecal midazolam significantly improves the duration and quality of spinal anesthesia and provides prolonged perioperative analgesia without any significant side effects and neurological damage [58-61]. Prochazka shared their decade long experience of using intrathecal midazolam in 2006 [62]. According to them, intrathecal midazolam is able to provide good analgesia in most patients and is a very suitable supplement for postoperative and long-term analgesia without demand of expensive systems (*Patient Controlled Analgesia and other drug infusion systems, etc*.). On the other hand, recent studies showed that intrathecal midazolam appears to improve perioperative analgesia and it can be useful and safe adjunct to bupivacaine for intrathecal analgesia during different surgical operations [35, 63-66].

Addition of preservative free midazolam to hyperbaric bupivacaine for spinal anesthesia in different surgical procedures/operations prolongs the duration of effective analgesia as compared to bupivacaine alone and delays the need for postoperative rescue analgesics without having any sedative effect, pruritus, or respiratory depression. The use of intrathecal midazolam also decreases the incidence of postoperative nausea vomiting (*PONV*). Moreover, intrathecal midazolam does not have any clinically significant effect on perioperative hemo‐ dynamics. A small diluted dose of preservative-free intrathecal midazolam *(<1mg/mL concen‐ tration and 1 to 2.5mg*) appears to have few systemic side effects and is free of short-term

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129

The use of spinal anesthesia is often limited by the unwillingness of patients to remain awake during surgery [69]. Spinal anesthesia provides anesthesia at the surgical site, yet unpleasant and uncomfortable patient experiences result from having to remain in the same position, prolonged duration of surgery or ambient noise in the operating room. To avoid spontaneous movements by an inadequately sedated patient that can interfere with the surgical procedure, intravenous sedative medications can be useful in patients who are positioned in specific postures that can be considered uncomfortable [70]. On the other hand, the goals of sedation during spinal anesthesia include rapid achievement of adequate sedation, its maintenance at a constant level during the surgical procedure and awakening the patient quickly at the end.

**4. Sedation in spinal anesthesia with intravenous midazolam**

This can be attained by continuous infusion of sedative drugs preceded by a bolus.

Conscious sedation is a minimally depressed level of consciousness that retains the patient's ability to maintain his or her airway independently and continuously, and to respond appropriately to physical stimulation and verbal command, produced by pharmacologic or non-pharmacologic methods, alone or in combination [71]. With conscious sedation only some of the centers in the medullary reticular formation and thalamus are depressed in a dose dependent manner [72]. Thus, this level of sedation provides the additional benefit of preser‐ vation of protective airway reflexes, especially in monitored anesthesia care. An ideal supple‐ mental sedative should provide effective anxiolysis, an easily controllable level of sedation, predictable depth of amnesia, a rapid and clear headed recovery, minimal intraoperative side effects, no evidence of cumulation and minimal postoperative side effects. Numerous agents have been used as sedative adjuvants to spinal anesthesia, each with their own advantages

The most widely used technique for administering sedation in regional anesthesia is the intermittent intravenous bolus dose technique. This technique has been shown to be associated with peaks and troughs in plasma concentration producing significant side effects and delayed recovery [73]. Continuous infusions have been proven to produce lesser side effects, faster recovery, easy controllability over the desired depth of sedation and, should the regional block

prove to be ineffective, easy conversion to general anesthesia [74, 75].

neurotoxicity.

and disadvantages.

Yegin et al. in 2004, conducted a study on the analgesic and sedative effects of intrathecal 2mg preservative free midazolam in perianal surgery under spinal anesthesia [37]. They found that the addition of bupivacaine produces a more effective and longer analgesia with a mild sedative effect in patients in the experimental group. One year later Agrawal et al. investigated postoperative pain relief following intrathecal administration of 1mg preservative free midazolam with bupivacaine in patients scheduled for elective lower abdominal, lower limb, and endoscopic urological surgeries [67]. They showed that intrathecal midazolam and bupivacaine provide longer duration of postoperative analgesia as compared to intrathecal bupivacaine alone, without prolonging time for dermatomal regression. Also, Prakash et al. [35] with Ho and Ismail [64] found that intrathecal midazolam appears to improve perioper‐ ative analgesia and reduce nausea and vomiting during caesarean delivery. On the other hand in 2011, Shadangi et al. concluded that the addition of preservative-free midazolam to bupivacaine intrathecally resulted in prolonged postoperative analgesia without increasing motor block [68].

Addition of preservative free midazolam to hyperbaric bupivacaine for spinal anesthesia in different surgical procedures/operations prolongs the duration of effective analgesia as compared to bupivacaine alone and delays the need for postoperative rescue analgesics without having any sedative effect, pruritus, or respiratory depression. The use of intrathecal midazolam also decreases the incidence of postoperative nausea vomiting (*PONV*). Moreover, intrathecal midazolam does not have any clinically significant effect on perioperative hemo‐ dynamics. A small diluted dose of preservative-free intrathecal midazolam *(<1mg/mL concen‐ tration and 1 to 2.5mg*) appears to have few systemic side effects and is free of short-term neurotoxicity.

#### **4. Sedation in spinal anesthesia with intravenous midazolam**

test tubes and the solution was examined for any change of pH and a reduction in the transparency of the solution [52]. Cerebrospinal pH was decreased to below 7.0 adding more than 3 mg of midazolam, more than 1.9 mL of 0.25% bupivacaine or 1.3 mL of the mixture. Cerebrospinal transparency by adding more than 0.7 mg of midazolam, 1.1 mL of 0.25% bupivacaine or 0.6 mL of the mixture. Midazolam in saline neither decreased the pH below nor reduced transparency. These results are very important so this study showed that clinically useful doses of intrathecal or epidural midazolam were not neurotoxic. In the same year, Gulec et al. showed that caudal administration of a bupivacaine-midazolam mixture produces a longer duration of postoperative analgesia than a bupivacaine-morphine mixture and bupivacaine alone [53]. Batra et al. in 1999, conducted a study on postoperative analgesia in patients undergoing knee arthroscopy following intrathecal administration of midazolam in combination with hyperbaric bupivacaine [54]. They demonstrated that this combination produces better postoperative analgesia. In 2001, Kim and Lee showed a dose-dependent effect of intrathecal midazolam [55]. Sen et al. reported that intrathecal midazolam produced significant postoperative pain relief together with antiemetic effect and tranquillity in patients undergoing caesarean section delivery [56]. Maharjan et al showed that caudal administration of midazolam-bupivacaine mixture significantly prolongs postoperative analgesia compared to bupivacaine alone in children undergoing genitourinary surgery [57]. Moreover, other studies have shown that addition of intrathecal midazolam significantly improves the duration and quality of spinal anesthesia and provides prolonged perioperative analgesia without any significant side effects and neurological damage [58-61]. Prochazka shared their decade long experience of using intrathecal midazolam in 2006 [62]. According to them, intrathecal midazolam is able to provide good analgesia in most patients and is a very suitable supplement for postoperative and long-term analgesia without demand of expensive systems (*Patient Controlled Analgesia and other drug infusion systems, etc*.). On the other hand, recent studies showed that intrathecal midazolam appears to improve perioperative analgesia and it can be useful and safe adjunct to bupivacaine for intrathecal analgesia during different surgical

Yegin et al. in 2004, conducted a study on the analgesic and sedative effects of intrathecal 2mg preservative free midazolam in perianal surgery under spinal anesthesia [37]. They found that the addition of bupivacaine produces a more effective and longer analgesia with a mild sedative effect in patients in the experimental group. One year later Agrawal et al. investigated postoperative pain relief following intrathecal administration of 1mg preservative free midazolam with bupivacaine in patients scheduled for elective lower abdominal, lower limb, and endoscopic urological surgeries [67]. They showed that intrathecal midazolam and bupivacaine provide longer duration of postoperative analgesia as compared to intrathecal bupivacaine alone, without prolonging time for dermatomal regression. Also, Prakash et al. [35] with Ho and Ismail [64] found that intrathecal midazolam appears to improve perioper‐ ative analgesia and reduce nausea and vomiting during caesarean delivery. On the other hand in 2011, Shadangi et al. concluded that the addition of preservative-free midazolam to bupivacaine intrathecally resulted in prolonged postoperative analgesia without increasing

operations [35, 63-66].

128 Topics in Spinal Anaesthesia

motor block [68].

The use of spinal anesthesia is often limited by the unwillingness of patients to remain awake during surgery [69]. Spinal anesthesia provides anesthesia at the surgical site, yet unpleasant and uncomfortable patient experiences result from having to remain in the same position, prolonged duration of surgery or ambient noise in the operating room. To avoid spontaneous movements by an inadequately sedated patient that can interfere with the surgical procedure, intravenous sedative medications can be useful in patients who are positioned in specific postures that can be considered uncomfortable [70]. On the other hand, the goals of sedation during spinal anesthesia include rapid achievement of adequate sedation, its maintenance at a constant level during the surgical procedure and awakening the patient quickly at the end. This can be attained by continuous infusion of sedative drugs preceded by a bolus.

Conscious sedation is a minimally depressed level of consciousness that retains the patient's ability to maintain his or her airway independently and continuously, and to respond appropriately to physical stimulation and verbal command, produced by pharmacologic or non-pharmacologic methods, alone or in combination [71]. With conscious sedation only some of the centers in the medullary reticular formation and thalamus are depressed in a dose dependent manner [72]. Thus, this level of sedation provides the additional benefit of preser‐ vation of protective airway reflexes, especially in monitored anesthesia care. An ideal supple‐ mental sedative should provide effective anxiolysis, an easily controllable level of sedation, predictable depth of amnesia, a rapid and clear headed recovery, minimal intraoperative side effects, no evidence of cumulation and minimal postoperative side effects. Numerous agents have been used as sedative adjuvants to spinal anesthesia, each with their own advantages and disadvantages.

The most widely used technique for administering sedation in regional anesthesia is the intermittent intravenous bolus dose technique. This technique has been shown to be associated with peaks and troughs in plasma concentration producing significant side effects and delayed recovery [73]. Continuous infusions have been proven to produce lesser side effects, faster recovery, easy controllability over the desired depth of sedation and, should the regional block prove to be ineffective, easy conversion to general anesthesia [74, 75].

Of the currently available benzodiazepines, midazolam has a fast onset and short recovery time, because of which it is one of the most widely used sedatives in spinal anesthesia. With a low context sensitive half time (*70 minutes for a four hour long infusion and up to 100 minutes for longer infusions*), it can be easily titrated to the needs of the patient, making its use well suited for ambulatory conscious sedation techniques [4, 76]. It produces good sedation and excellent amnesia but has no specific analgesic properties [77].

**5. Conclusion**

respiration during spinal anesthesia.

clinically acceptable analgesic properties.

mies. Indian J Anaesth 2010;54:24-8.

**Author details**

Beyazit Zencirci\*

**References**

sia.

Spinal anesthesia has the advantage of being able to maintain spontaneous breathing as well as relaxing the necessary muscles for surgery. However, the time limit and patient's anxiety of spinal anesthesia are important disadvantages. On the other hand, the impediments to the effective use of spinal anesthesia are the predictable decreases in arterial blood pressure and heart rate through the accompanying sympathectomy with its attendant vasodilatation and blockade of cardio accelerator fibres. Another clinically important impediment to successful block is inadequate sedation. Adjunctive drugs are used to decrease anxiety, alleviate discom‐ fort, improve hemodynamic stability and induce a feeling of calmness during spinal anesthe‐

Midazolam in Spinal Anesthesia — Intrathecal or Intravenous?

http://dx.doi.org/10.5772/58750

131

When using sedative medication during spinal anesthesia, the anesthesiologist attempts to titrate the drug to optimize patient comfort while maintaining cardiorespiratory stability and intact protective reflexes. Morever, adequate sedation in spinal anesthesia relieves the anxiety of the patient, improves physiological and psychological stress, and increases the satisfaction of the surgeon, anesthetist and patient. Midazolam is most frequently used as the agent for sedation. It is often used intravenously in single doses of between 0.5 mg and 2.5 mg. Mida‐ zolam provides rapidly induced sedation and amnesia with stable hemodynamics and

Moreover, midazolam has been shown to have antinociceptive effects when administered intrathecally, both in laboratory animals and in humans. Intrathecal injection up to 2 mg midazolam have been reported without adverse effects. The paucity of studies on intrathecal midazolam warrants caution in elderly patients, the obese, and those who are already on other sedatives. When intrathecal midazolam is used, all patients should be closely monitored intra and postoperatively. In brief, intrathecal preservative free midazolam appears safe and has

Marash Life Hospital – Department of Anesthesiology & Reanimation, Turkey

[1] Zencirci B. Postdural puncture headache and pregabalin. J Pain Res 2010;3:11-4.

[2] Ahmed F, Garg A, Chawla V, Khandelwal M. Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterecto‐

Benzodiazepines cause greater depression of upper airway muscle tone in the elderly, resulting in a higher incidence of airway obstruction [78, 79]. On the other hand, the synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, facilitate better sedation and analgesia. However, the combination of these drugs also enhances their respi‐ ratory depression and may lead to airway obstruction or apnea [80]. Administration of oxygen to all the patients during sedation and immediate relief of airway obstruction prevented the occurrence of oxygen desaturation. A smaller volume bolus and a slow infusion rate avoided apnea.

Bolus administration of midazolam 0.05 mg/kg was reported to give enough amnesia and sedation without any adverse effects on hemodynamics and respiration [80]. With this method, patients did not respond to verbal command but recovered in 25 minutes [81] and opened their eyes spontaneously in 47 minutes [82]. As long as patients closed their eyes, amnesic effect was kept and when they opened their eyes, additional midazolam 1 mg (*approximately 18 mcg/ kg*) was enough for patient's comfort [82]. However, bolus administration of sedative can not provide constant level of sedation. In contrast, continuous infusion can provide constant sedation level but usually prolongs onset time of sedation compared with the intermittent bolus technique [83]. Different studies showed that during spinal anesthesia, midazolam (*1-2 mg given and followed by 0.1-0.5 mg/kg/hr intravenously*) provides rapidly induced sedation and amnesia with stable hemodynamics and respiration. Oxygen must be administered at 3-6 L/min through a mask during the procedure. Intraoperative monitoring must include electro‐ cardiography, pulse oxmetry, noninvasive sphygmomanometry, and capnography.

Midazolam is considered safe even at high doses and, at equipotent doses, it affects (*via GABA*) the central nervous system in a similar fashion [84]. GABA receptors are found in different parts of the brain. The sedative effects of the benzodiazepines are mediated by the brainstem GABA receptors that inhibit the ascending pathways that activate the brain cortex. The ataxia and memory impairment are mediated by GABA receptors in the cerebellar, hippocampal, and forebrain areas. While hypnosis or sedation is always achieved after appropriate individually based doses, anxiolysis is seldom transformed into anxiety, restless‐ ness, rage or a myriad of uncontrolled behaviours (*midazolam paradox*)[84]. The relationship of the paradoxical reaction to alteration of the cholinergic homeostasis, serotonin levels, the role of genetics, and gamma-aminobutyric acid receptor configuration are suspect [85]. Such paradoxical reactions may harm the unconscious or semiconscious patient. Low dose of flumazenil (*0.2-0.3 mg, range 0.1-0.5 mg*) completely reverses midazolam-induced paradoxical reactions and they are more frequent in older patients [84, 85].

#### **5. Conclusion**

Of the currently available benzodiazepines, midazolam has a fast onset and short recovery time, because of which it is one of the most widely used sedatives in spinal anesthesia. With a low context sensitive half time (*70 minutes for a four hour long infusion and up to 100 minutes for longer infusions*), it can be easily titrated to the needs of the patient, making its use well suited for ambulatory conscious sedation techniques [4, 76]. It produces good sedation and

Benzodiazepines cause greater depression of upper airway muscle tone in the elderly, resulting in a higher incidence of airway obstruction [78, 79]. On the other hand, the synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, facilitate better sedation and analgesia. However, the combination of these drugs also enhances their respi‐ ratory depression and may lead to airway obstruction or apnea [80]. Administration of oxygen to all the patients during sedation and immediate relief of airway obstruction prevented the occurrence of oxygen desaturation. A smaller volume bolus and a slow infusion rate avoided

Bolus administration of midazolam 0.05 mg/kg was reported to give enough amnesia and sedation without any adverse effects on hemodynamics and respiration [80]. With this method, patients did not respond to verbal command but recovered in 25 minutes [81] and opened their eyes spontaneously in 47 minutes [82]. As long as patients closed their eyes, amnesic effect was kept and when they opened their eyes, additional midazolam 1 mg (*approximately 18 mcg/ kg*) was enough for patient's comfort [82]. However, bolus administration of sedative can not provide constant level of sedation. In contrast, continuous infusion can provide constant sedation level but usually prolongs onset time of sedation compared with the intermittent bolus technique [83]. Different studies showed that during spinal anesthesia, midazolam (*1-2 mg given and followed by 0.1-0.5 mg/kg/hr intravenously*) provides rapidly induced sedation and amnesia with stable hemodynamics and respiration. Oxygen must be administered at 3-6 L/min through a mask during the procedure. Intraoperative monitoring must include electro‐

cardiography, pulse oxmetry, noninvasive sphygmomanometry, and capnography.

reactions and they are more frequent in older patients [84, 85].

Midazolam is considered safe even at high doses and, at equipotent doses, it affects (*via GABA*) the central nervous system in a similar fashion [84]. GABA receptors are found in different parts of the brain. The sedative effects of the benzodiazepines are mediated by the brainstem GABA receptors that inhibit the ascending pathways that activate the brain cortex. The ataxia and memory impairment are mediated by GABA receptors in the cerebellar, hippocampal, and forebrain areas. While hypnosis or sedation is always achieved after appropriate individually based doses, anxiolysis is seldom transformed into anxiety, restless‐ ness, rage or a myriad of uncontrolled behaviours (*midazolam paradox*)[84]. The relationship of the paradoxical reaction to alteration of the cholinergic homeostasis, serotonin levels, the role of genetics, and gamma-aminobutyric acid receptor configuration are suspect [85]. Such paradoxical reactions may harm the unconscious or semiconscious patient. Low dose of flumazenil (*0.2-0.3 mg, range 0.1-0.5 mg*) completely reverses midazolam-induced paradoxical

excellent amnesia but has no specific analgesic properties [77].

apnea.

130 Topics in Spinal Anaesthesia

Spinal anesthesia has the advantage of being able to maintain spontaneous breathing as well as relaxing the necessary muscles for surgery. However, the time limit and patient's anxiety of spinal anesthesia are important disadvantages. On the other hand, the impediments to the effective use of spinal anesthesia are the predictable decreases in arterial blood pressure and heart rate through the accompanying sympathectomy with its attendant vasodilatation and blockade of cardio accelerator fibres. Another clinically important impediment to successful block is inadequate sedation. Adjunctive drugs are used to decrease anxiety, alleviate discom‐ fort, improve hemodynamic stability and induce a feeling of calmness during spinal anesthe‐ sia.