Intrathecal Administration Of Midazolam Research Articles

When Data Are Not Proof

In this issue, Prochazka, Ales, and Prachazkova reported their experience with intrathecal administration of midazolam for failed back surgery syndrome [1]. During the review process, there were disputes about this article between the referees and the authors. The referees welcomed the data but not the conclusions. The authors contend that they provide evidence of effectiveness of this intervention. In their correspondence, they cited other studies that also claimed effectiveness. However, the authors misunderstood the concerns of the referees. Post hoc , propter hoc is a common fallacy and illusion in clinical practice. Just because a patient improved after a treatment does not mean that they improved because of the purported effects of the treatment. In the present case, the authors contend that the improvements must have been due to the midazolam. Quoting others who make the same claim is not an evidence that midazolam is effective. Doing so only refers to others who suffer the same illusion. For a drug to be regarded as effective, we need data on its attributable effect, i.e., …

Interaction between midazolam and serotonin in spinally mediated antinociception in rats

Intrathecal administration of serotonin (5-HT) is antinociceptive through the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors. Therefore, 5-HT would interact with the GABA agonist, midazolam, which is well known to exert spinally mediated antinociception in the spinal cord. The present study investigated the antinociceptive interaction between spinally administered 5-HT and midazolam, using two different rat nociceptive models. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and paw flinches induced by formalin injection after the intrathecal administration of midazolam or 5-HT, or the midazolam/ HT combination. The effects of the combination were tested by isobolographic analysis, using the combination of each 1, 1/2, 1/4, 1/8, and 1/16 of the 50% effective dose (ED50). The total fractional dose was calculated. Behavioral side effects were also examined. 5-HT alone and midazolam alone both showed dose-dependent antinociception in both the tail flick test and the formalin test. The ED50 of the combination was not different from the calculated additive value either in the tail flick test or in phase 2 of the formalin test, but it was significantly smaller than the calculated additive value in phase 1 of the formalin test. The total fractional dose value was 0.90 in the tail flick test, 0.093 in phase 1 of the formalin test, and 1.38 in phase 2 of the formalin test. The agitation, allodynia, or motor disturbance observed with either agent alone was not seen with the combination treatment. The antinociceptive effects of intrathecal midazolam and 5-HT were additive on thermal acute and inflammatory facilitated stimuli, and synergistic on inflammatory acute stimulation.

Midazolam Potentiates Nociceptive Behavior, Sensitizes Cutaneous Reflexes, and Is Devoid of Sedative Action in Neonatal Rats

The significant postnatal maturation of gamma-aminobutyric acid signaling in the developing brain is likely to have important implications for infant pain processing. Gamma-aminobutyric acid receptor activation evokes analgesia and sedation in the adult, but the impact of immature gamma-aminobutyric acid signaling on modulators of the gamma-aminobutyric acid type A receptor, such as the benzodiazepines, is not known in infants. Nociceptive processing was measured using behavioral and electrophysiological recordings of hind limb flexor withdrawal threshold and magnitude to mechanical and thermal stimulation of the hind paw. The effects of midazolam (0.1-10 mg/kg subcutaneously, 0.1 mg/kg intrathecally) or saline treatment were compared in rats aged 3, 10, 21, and 40 days (adult). The sedative action of midazolam was assessed at each age using righting reflex latencies. Midazolam dose-dependently decreased mechanical reflex thresholds and increased mechanical and thermal reflex magnitudes in neonates. In older rat pups and adults, midazolam had the reverse effect, increasing thresholds and decreasing reflex magnitude. These differences were mediated supraspinally; intrathecal administration of midazolam did not affect flexion reflexes at any age. Midazolam had no sedative action in the youngest rats; sedation increased gradually through postnatal development. The results show a striking reversal in the effects of midazolam on nociception and sedation in rats between postnatal days 3 and 10. Midazolam fails to sedate young rats and sensitizes their flexor reflex activity. The sedative and desensitizing effects of midazolam are not observed until later in life after maturation in supraspinal centers. The results indicate a need to better understand the pharmacology of drugs used routinely in neonatal intensive care.

Acute Phase Histopathological Study of Spinally Administered Midazolam in Cats

Acute Phase Histopathological Study of Spinally Administered Midazolam in Cats

Antinociceptive activity of midazolam in sheep.

The purpose of this study was to examine the effects of midazolam on the nociceptive threshold responses in sheep. The intravenous administration of midazolam (0.1-0.3 mg/kg) produced a significant dose-dependent elevation of the mechanical and thermal nociceptive thresholds. The intravenous administration of flumazenil (20 micrograms/kg) markedly attenuated the antinociceptive activity of midazolam in the mechanical nociceptive test, whereas intravenous naloxone (0.2 mg/kg) had no significant effect on midazolam-mediated analgesia. The intrathecal administration of midazolam (1 mg), via chronically implanted cervical subarachnoid catheters, produced a significant elevation in the mechanical threshold responses. These results indicate that midazolam has antinociceptive actions in the sheep and suggest that this effect is, at least partially, mediated at the spinal level.

Effect on morphine-induced catalepsy, lethality, and analgesia by a benzodiazepine receptor agonist midazolam in the rat

Previously we have shown that intrathecal administration of midazolam can increase or decrease morphine-induced antinociception, depending upon relative concentration of these drugs by modulating spinal opioid receptors, and it also can inhibit morphine-induced tolerance and dependence in the rat. Now we report that midazolam also influences catalepsy, lethality, and analgesia induced by morphine in the rat. In the acute treatment, animals were first treated with saline or midazolam (0.03 to 30.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (1.0 to 100.0 mg/kg, b.wt., SC). The catalepsy was measured 60 min after the second injection and lethality was checked after 24 h. Midazolam injection increased the morphine-induced catalepsy and lethality. In the chronic treatment, animals were injected with two injections daily for 11 days. The first injection consisted of saline or midazolam (0.03 to 3.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (10.0 mg/kg, b.wt., IP) was given. Lethality, antinociception, and body weight were measured. Chronic morphine treatment also increased lethality in a dose-dependent manner. Chronic treatment with midazolam and morphine increased the antinociception on day 11, as measured in the tail-flick and hot-plate tests. Midazolam administration also prevented the morphine-induced weight loss. These results suggest a strong interaction between midazolam and morphine in altering catalepsy, lethality, and analgesia in rat.