Page 182 Acute Pain Management

5.3.4 Midazolam

Midazolam, the preservative‐free preparation, has been proposed as a potential spinal
analgesic due to its action on GABA A receptors. It is not approved for this indication and
efficacy and safety issues remain unclear.
Reports of intrathecal midazolam administration have appeared in the literature for many
years, despite concerns regarding potential neurotoxicity (Yaksh & Allen, 2004). Early clinical
series (Tucker, Lai et al, 2004 Level III‐2; Tucker, Mezzatesta et al, 2004 Level III‐2) and laboratory
investigations (Johansen et al, 2004) suggested a low risk of toxicity — neurotoxic damage was
not seen in sheep and pigs given continuous intrathecal midazolam (Johansen et al, 2004) and a
1‐month questionnaire follow‐up of patients who had received intrathecal midazolam failed to
show any evidence of neurological or urological complications (Tucker, Lai et al, 2004 Level III‐2).
A meta‐analysis of intrathecal midazolam in perioperative and peripartum patients showed
the addition of intrathecal midazolam (typically 2 mg or more) to other spinal medications
reduced the incidence of nausea and vomiting and delayed the time to request for rescue
analgesia, but had little effect beyond 12 hours (Ho & Ismail, 2008 Level I). The incidence of
neurological symptoms after intrathecal midazolam was uncommon (1.8%) and did not differ
from placebo (Ho & Ismail, 2008 Level I).There are insufficient data to exclude the possibility of
long‐term neurological complications from intrathecal midazolam, although none have yet
been reported.
Another study reported that the addition of subarachnoid midazolam for labour pain
CHAPTER 5 (Tucker, Mezzatesta et al, 2004 Level II). Combining intrathecal midazolam (2 mg) with
produced no effect on its own, but potentiated the analgesic effect of intrathecal fentanyl

bupivacaine for Caesarean section significantly prolonged the block and reduced nausea
without CV or neurological side effects (Prakash et al, 2006 Level II).
Midazolam added to bupivacaine for epidural infusion improved analgesia but increased
sedation (Nishiyama et al, 2002 Level II). In patients having a gastrectomy, single dose
preoperative epidural midazolam combined with ketamine improved analgesia and prolonged
the time to rescue analgesia compared with epidural ketamine or placebo, with no significant
adverse effects (Wang et al, 2006 Level II).
Midazolam has been added to caudal epidural analgesia in paediatric surgery; age‐related
toxicity issues have not been addressed. In combination with bupivacaine it prolonged
postoperative analgesia (Kumar et al, 2005 Level II; Ansermino et al, 2003 Level I).

5.3.5 Neostigmine
Neostigmine acts as a spinal analgesic by potentiation of muscarinic cholinergic activity. In a
literature review of animal and human studies there was no evidence of neurotoxicity with
spinal neostigmine (Hodgson et al, 1999).
Intrathecal neostigmine for perioperative and peripartum analgesia resulted in a slight
improvement in pain scores and reduced the need for rescue medication; however, it
increased nausea and vomiting (OR 5), bradycardia requiring atropine (OR 2.7) and anxiety,
agitation and restlessness (OR 10.3) (Ho et al, 2005 Level I). The authors concluded that the
significant side effects outweighed any clinical benefit.
Epidural neostigmine combined with an opioid reduced the dose of epidural opioid that is
required for analgesia but there may not be any decrease in opioid‐related side effects
compared with the opioid alone (Walker et al, 2002 Level I). Epidural neostigmine in the
obstetric population improved postoperative analgesia in most studies without increasing the
incidence of adverse events (Habib & Gan, 2006 Level I). Epidural neostigmine combined with

134 Acute Pain Management: Scientific Evidence