Intrathecal opioids, potency and lipophilicity

McQuay, Henry J; Sullivan, Ann F.; Smallman, Karen; Dickenson, Anthony H.

doi:10.1016/0304-3959(89)90118-8

Cited by 149 publications

(27 citation statements)

References 9 publications

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“…Also, the degree of lipophilicity could help to correlate the difference between the ED50 of the opioids. Consequently, high-efficacy ligands, such as fentanyl and methadone possesses a higher ED 50 compared to lower efficacy ligands such as morphine with a lower ED 50 [2],[27]. …”

Section: Discussionmentioning

confidence: 99%

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

et al. 2014

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BackgroundOpioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated.ResultsThe potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes.ConclusionThese results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

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Section: Discussionmentioning

confidence: 99%

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

et al. 2014

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“…Administration of substances into the CSF of the spinal cord is often ineffective for the treatment of intracranial lesions because of rapid CSF-to-blood transfer (Bernards, 1999). Small, lipid-soluble molecules in particular are able to quickly cross the capillaries in the CNS-to-blood direction (McQuay et al, 1989;de Lange et al, 1993), just as they can rapidly cross in the blood-to-CNS direction. However, recent evidence has suggested that proteins administered i.t.…”

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confidence: 99%

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

McCarthy

Banks²,

Farrell

et al. 2002

J Pharmacol Exp Ther

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Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcuate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with 68 Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with 68 Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation.

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“…A particular aim is to reduce motor block and its associated problems in labour [ 1, 21. There have been many studies expounding the virtues of different opioids in this situation, but a major problem is that, in the published comparisons of opioids, there has been little attempt to achieve equi-analgesic doses [3]. Unless equi-analgesia is achieved, comparisons of efficacy and side-effect incidence have little meaning.…”

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confidence: 99%

Epidural infusion of alfentanil or diamorphine with bupivacaine in labour—a dose finding study

Hill¹,

McCarthy²,

Bali³

1995

Anaesthesia

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SummaryFollowing induction of epidural analgesia with 0.3 75% bupivacaine, 120 healthy parturients were randomly assigned in a double blind fashion to one of eight infusion groups. All received 8 m1.h-' of 0.125% bupivacaine either alone (control group), or with alfentanil at 133, 266 or 400pg.h-' (groups AI-A3) or with diamorphine at 133, 266, 400 or 533pg.h-' (groups D1-04). Significantly longer top-up intervals were achieved with the two highest doses of both alfentanil and diamorphine when compared with bupivacaine alone Cp < 0.01), making the minimum effective doses 266 pg.h-' of alfentanil and 400 pg.h-' of diamorphine. Perineal analgesia was better in all the opioid groups compared with the control group Cp < 0.05). The intensity of motor block was greater in the controlgroup (j < 0.05). The incidence ofpruritus didnot differ between groups. The highest dose of diamorphine caused significantly more nausea. No significant neonatal side-effects were demonstrated.

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Intrathecal opioids, potency and lipophilicity

Cited by 149 publications

References 9 publications

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

Epidural infusion of alfentanil or diamorphine with bupivacaine in labour—a dose finding study

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