Intrathecal Clonidine as Adjuvant for Labor Analgesia, Spinal Anesthesia, and Postoperative Analgesia in Caesarean Section

Spinal adjuvants drugs are use to enhance analgesia and anesthesia in several clinical scenarios. Clonidine has been used in anesthesia since 1982 to reduce needs of anesthetics, to provide cardiovascular stability, for anxiolysis, for sedation, and to treat pain. Although its spinal use in obstetrics patients still controversial, there is sufficient information to consider spinal clonidine as a safe adjuvant to enhance spinal labour analgesia and to improve spinal anesthesia for caesarean section, and also to augment spinal postoperative anesthesia after surgical delivery. Using recommended doses, the usual side effects of subarachnoid clonidine are moderate hypotension, non harm fetal arrhythmias, and moderate mother sedation.


Introduction
The role of anesthesiologist in obstetric practice has many duties such labour analgesia, anesthesia for vaginal delivery, for caesarean section, for abortion, for non-obstetric surgeries during pregnancy, postoperative analgesia, and at times assist in the resuscitation of the newborn. Neuraxial analgesia is a popular technique to manage labor pain and has being considered as the gold standard in obtaining maternal pain relief during labor. It can be done in three different ways: epidural, spinal and combining epidural-spinal. Each one has its advantages and side effects on the mother and/or the fetus-newborn [1][2][3]. Increase in the incidence of fetal heart rate changes after intrathecal analgesia has been reported, though fetal bradycardia caused by labor analgesia-anesthesia does not usually increase the risk of emergent operative deliveries.
Nowadays spinal anesthesia is the technique of choice for caesarean section. It is safe, effective, easy to perform and inexpensive. Its main limitations are its short duration of action and do not provide prolonged postoperative analgesia when it is performed only with local anesthetics [4][5][6]. Adding adjuvant drugs to intrathecal local anesthetics improves quality and duration of spinal blockade, and prolongs postoperative analgesia. It is also possible to reduce dose of local anesthetics, as well as total amount of systemic postoperative analgesics. Spinal clonidine has been used for labor analgesia, to enhance spinal anesthesia during caesarean 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 late respiratory depression secondary to rostral opioid distribution. Theoretically, it could also reduce the fetal bradycardia [7][8][9][10][11][12]. This mini-review is an up to date of the pros and cons of the use of spinal clonidine in obstetric patients.

Clonidine
This alpha 2 adrenergic receptor agonist was developed in 1962 as an effort to make a nasal decongestant. It was marketed as antihypertensive in 1972 since its effect to decrease sympathetic outflow from CNS and to diminish pre-synaptic nor-epinephrine release [13]. It is an imidazoline derivative that exists as a mesomeric compound, with a molecular weight of 266.56, chemical name is Benzenamine,2,6-dichloro-N-2-imidazolindinylidene monohydrochloride and 2-((2,6-dichlorophenyl)imino)imidazolidine mono-hydrochloride. Figure 1 shows its structural formula (C 9 H 9 Cl 2 N 3 ·HCl). Clonidine stimulates alpha2 adrenoreceptors in the brain and spinal cord, resulting in reduction of sympathetic outflow from the central nervous system and in decreased in peripheral resistance, renal vascular resistance, plasma renin activity, heart rate, cardiac output, and blood pressure. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent. Plasmatic level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration, approximately 75% is bioavailable in men, about 40-60% of the absorbed dose recovered unchanged in the urine in 24 hours. About 50% of the absorbed dose is metabolized in the liver. Severe adverse side effects are infrequent, and well tolerated in most patients. Sedation and dry mouth are the most common side effects, are usually related to dose and duration of administration [14,15].

Adjuvant for spinal labor analgesia
Labor pain encounter is affected by physiological and psychosocial factors and usually is so intense that most women require pain relief. Nowadays analgesia for labor delivery is safer than ever. An ideal labor analgesia plan needs to embrace newer procedures and adjuvant drugs in order to facilitate ambulation, excellent pain relief, patient comfort and no deleterious side effects to either the parturient or the fetus-neonate. It can be done using non-pharmacological measures and/or employing pharmacological products [1,16,17]. At the present time the advances in pharmacology of labor analgesia converge on the 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 anesthetics, and addition of neuraxial adjuvants like opioids, neostigmine, and clonidine [18][19][20][21][22][23][24].
A single spinal injection of local anaesthetics is not universally recommended for labour analgesia due to its short time of duration. In order to overcome this limitation, several drugs have been used as adjuvants to local anesthetics. Opioids are the most used drugs, combined with small doses of bupivacaine, ropivacaine or levobupivacaine. Alpha2 adrenergic agonists, clonidine and dexmedetomidine, have been investigated to enhance quality and duration of spinal local anesthetics in many clinical scenarios, including obstetrics patients, with a diversity of results.

Spinal clonidine for labor analgesia
In 1989, Eisenach and coworkers demonstrated that epidural clonidine did not affect sheep fetus [9]; they studied the acute maternal and fetal effects of 300 µg epidural clonidine in near term ewes, and found that epidural clonidine augmented maternal and fetal serum glucose by 30% one hour after injection, without changes in cortisol and arterial blood gas tension. There were minor decreases (10-15%) in heart rate in ewe and fetus, without altering maternal and fetal blood pressure, intra-uterine pressure, or uterine blood flow. Maternal and fetal serum clonidine concentrations peaked at 58±8 and 73±5 min following peridural injection, respectively, and declined with similar half-lives. Heart rate correlated negatively with serum clonidine concentration in both ewe and fetus (p˂.05). Since this initial research, many clinical studies have been done using neuroaxial clonidine mixed with local anesthetics and/or opioids. A year later, these same researchers studied the effects of high doses of intrathecal clonidine in sheep [25] and found that clonidine altered maternal blood pressure in a biphasic mode (hypotension with lower dose and return to baseline values with higher dose, it also produced a dose dependent decrease in fetal and maternal heart rate. They mentioned that fetal bradycardia may limit the efficacy of spinal clonidine if used more than 10 µg/ kg in obstetrics. Most studied doses of intrathecal clonidine for labor analgesia range from 15 to 45 µg mixed with opioids and/or local anesthetics. The first clinical report on intrathecal clonidine for labour analgesia is an abstract published by Chiari et al. [16], using 100 µg alone or combined with sufentanil 2 µg versus sufentanil alone. Clonidine analgesia was superior and longer than sufentanil, and the mixture of both drugs produced more profound and lasting analgesia but more hypotension. In a preliminary open-label study done by Mercier et al. [6] comparing sufentanil 5 µg+ clonidine 30 µg versus sufentanil 5 µg alone injected intrathecally to alleviate pain during the first stage of labor, the authors demonstrated that clonidine potentiate labor analgesia and side effects such hypotension, maternal pruritus and sedation were similar in both groups. In a second research of the same group [10], they 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. [7] found that 30 µg of intrathecal clonidine plus 2.5 or 5 µg intrathecal sufentanil increased the duration of labor analgesia during the first stage without undesirable maternal or fetal effects. In a 30 randomized patients [26], comparing subarachnoid clonidine 50 µg, plus sufentanil 7.5 µg and bupivacaine 2.5 mg versus a mixture of sufentanil-bupivacaine without clonidine in first stage labour pain, the researchers were able to demonstrated significantly prolonged analgesia in those women treated whit clonidine (197±70 versus 132±39 min; p=0.004). Motor block, sedation and hypotension were not critical and similar in all patients. Sia [27] compared 15 and 30 µg clonidine with a control group with no clonidine. All randomized parturient were spinally injected with sufentanil 5 µg and bupivacaine 1.25 mg to induce labor analgesia in 48 patients. Clonidine 15 and 30 µg produced an extended duration of analgesia compared with sufentanilbupivacaine alone (144±27.9, 165 ± 31.8 versus 111±21.9 min, respectively, p< 0.01). In addition, both doses of clonidine induced a more rapid onset and higher quality of analgesia. A higher cephalad sensory block was detected with the higher clonidine dose (median T3 versus T4, p < 0.05). Sedation and hypotension were more commonly with 30 µg than in either no clonidine or clonidine 15 µg (9 versus 2.5 and 9 versus 1.3, respectively, p < 0.05). In Indonesia [8], a study including 62 laboring women (45 primigravidas and 17 multigravidas) mixing spinal bupivacaine 2.5 mg morphine 250 µg and clonidine 45 µg found excellent analgesia with maternal satisfaction in 92%. Significantly, 49 patients (79%) stated that they would select the same technique for future labor pain. Labbene et al. [11] added clonidine 15 µg to 2.5 mg isobaric bupivacaine and 5 µg sufentanil during combined spinal-epidural analgesia resulting in extended duration of analgesia without increasing side effects.
Chiari et al. [28] did the first study using spinal clonidine as a sole drug for labor analgesia; in 36 parturient 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 i.v. 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 [29][30][31]. The study done by Paech et al. [32] 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. Two Brazilian studies [33,34] found that 30 µg clonidine added to hypobaric or hyperbaric bupivacaine and sufentanil did not prolonged analgesia duration. There was a higher incidence of hypotension in patients receiving isobaric bupivacaine. To avoid hypotension due to the combination of spinal clonidine-opioids-diluted local anesthetics, epidural clonidine can be used in doses of 75 µg [35].
Fetal heart rate abnormalities are not exclusive of spinal clonidine, have also been described with opioids such sufentanil [36,37] Usually fetal heart rate changes do not affect neonatal outcome in healthy population. When low doses of clonidine with or without opioids are used for spinal labor analgesia, we must remember that at the end of pregnancy there is a degree of auto analgesia mediated by endorphins [38]. Even though neuraxial analgesia is the most efficient and safest mode of labor analgesia [1][2][3]39], the use of spinal clonidine mixed with opioids and/or local anesthetics must be must be used cautiously to avoid hypotension. The optimal dose of subarachnoid clonidine to augment labor analgesia obtained with the spinal mixture of opioids-local anaesthetic range from 15 to 30 µg larger doses would induce more deleterious side effects.

Spinal clonidine for cesarean section
Although some controversies, nowadays spinal anesthesia is the most used technique for cesarean section [40][41][42]. 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 anesthetics, and to prolong postoperative analgesia. It can also be combined with intrathecal opioids, as there is a synergic effect.
A double blind study [43] carried out to evaluate the analgesic effect of clonidine in patients undergoing elective cesarean section, doses of 150 µg were injected 45 min after general anesthesia 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. Filos et al. [44] using 150, 350 and 450 µg of spinal clonidine performed to evaluate the dose-response hemodynamic and analgesic profiles in the immediate postoperative period of caesarean section under general anesthesia. 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 stability after 300 and 450 µg suggested a pressor consequence at peripheral sites. Other studies have found that 75 µg is a safe dose; prolong the anesthetic block and enhance postoperative analgesia, with minimal side effects and no harm to the newborn [45][46][47]. In a randomized, double blind, dose finding study, Peach et al. [48] 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 100 µg 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 [49] 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 min 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. In a recent study done by Khezri et al. [46], the authors compared three groups: clonidine 75 µg plus bupivacaine 10mg, fentanyl 25 µg plus bupivacaine 10mg, and bupivacaine 10mg plus saline as control group. They found that spinal clonidine prolonged duration of anesthesia (275.10±96.09 versus 192.33±30.36 versus 211.73±74.80 respectively). Also, mean time for first analgesic request was longer in clonidine group; however the total analgesic consumption within the first postoperative day were similar to fentanyl treated group. In another study with clonidine 75 µg plus hyperbaric bupivacaine prolongs spinal anesthesia and improves early postoperative analgesia after caesarean section, but does not diminish morphine needs during the first 24 hours of the postoperative period [50]. 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 [51]. As a single drug, subarachnoid clonidine is not recommended for anesthesia neither for post caesarean analgesia.

Conclusion
Should we administer intrathecal clonidine in obstetric patients? This same question was asked in an editorial published in 2000; D´Angelo [52] comments the results of Paech et al. [53] on epidural clonidine for labor pain and recommends further studies before taking clonidine as part of our armamentarium in obstetric patients. Under the results of subsequent clinical investigations done by many authors in different countries, I think that intrathecal clonidine is a safe drug in obstetric patients when mentioned doses are observed. So, if the answer to that question is yes, what is the ideal dose for labor analgesia, for spinal anesthesia for caesarean section, or for postoperative analgesia? We still need more clinical studies to adequately respond to this question. Moreover, we have to keep in mind that the FDA maintains its recommendation not to use epidural clonidine in obstetrics. This organization does not mention the use of intrathecal clonidine in this clinical scenario.