Modelling concentration–analgesia relationships for morphine to evaluate experimental pain models

Sverrisdóttir, Eva; Foster, David J. R.; Upton, Richard N.; Olesen, Anne Estrup; Lund, Trine Meldgaard; Gabel-Jensen, Charlotte; Drewes, Asbjørn Mohr; Christrup, Lona Louring; Kreilgaard, Mads

doi:10.1016/j.ejps.2014.10.003

Cited by 12 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effect was delayed, and a model with an effect compartment with the equilibration half time fixed to 0.5 hours (Bouw et al, 2000; Sverrisdottir et al, 2014) was statistically superior to a model with an equilibration half time fixed to 0.28 hours (P = 0.014) (Inturrisi and Colburn, 1986), or a model without an effect compartment (P = 0.026). A model with only morphine concentrations linked to analgesia was superior to models with M6G concentrations (P < 0.001), or a combination of morphine and M6G concentrations (P < 0.001) linked to effect.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies with morphine and other opioids in experimental pain settings have demonstrated the importance of detecting placebo effect (Juul et al, 2014; Ravn et al, 2014; Sverrisdottir et al, 2014), which is generally only possible in an experimental pain setting. These studies showed that it is essential to understand the placebo response and the changes in baseline over time in order to identify the true drug effect.…”

Section: Discussionmentioning

confidence: 99%

“…To describe the morphine effect, structural models of linear, log-linear, E max , and sigmoidal E max functions of PIPP score versus either plasma concentration (direct effect) or effect compartment concentrations (delayed effect) was tested. The equilibration rate constant between the central compartment and the effect compartment, k e 0 , was estimated or fixed to a literature value (Bouw et al, 2000; Sverrisdottir et al, 2014). Normally or log normally distributed BSV was tested as appropriate for the different structural model parameters.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic models of morphine and its metabolites in neonates:

Knøsgaard

Foster

Kreilgaard

et al. 2016

European Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23–32 weeks) received a loading dose of morphine (50–100 μg/kg), followed by a continuous infusion (5–10 μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic models of morphine and its metabolites in neonates:

Knøsgaard

Foster

Kreilgaard

et al. 2016

European Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

“…22 For human studies of the thermal pain stimulus response, the primary outcome was the area under the pain intensityestimulus temperature curve; the study was powered to detect a 12% difference in this area between postpartum and control groups, an effect size observed with pharmacological interventions of approved analgesics. 23 For capsaicin-evoked hypersensitivity, the primary outcome was the area of hyperalgesia; the study was powered to detect a 33% difference in this area between groups, an effect size observed with pharmacological interventions of approved analgesics. 24,25 The primary outcome for the CPM study was the strength of CPM; the study was powered to detect a difference of 55% in CPM strength between groups.…”

Section: Primary Outcomesmentioning

confidence: 99%

Capsaicin-induced pain and sensitisation in the postpartum period

Street

Harris

Curry

et al. 2019

British Journal of Anaesthesia

View full text Add to dashboard Cite

Background: Recovery from Caesarean delivery in women and surgical nerve injury in animals after delivery is more rapid than expected, an effect reversed in animals by spinal injection of an oxytocin receptor antagonist. We hypothesised that endogenous modulation of acute pain is altered postpartum. Methods: Endogenous inhibition of acute pain in a conditioned pain modulation paradigm or endogenous sensitisation by topical capsaicin was tested in women who were breastfeeding 10e14 days after Caesarean delivery and age-matched controls (n¼80 total: 20 per group and 20 per test). The study was powered to detect a difference in area of hyperalgesia after capsaicin of 33%. Capsaicin-evoked pain was recorded in women, and capsaicin-evoked mechanical hypersensitivity was measured in rats 48 h after delivery and in age-matched female and male animals. Results: There was no effect of the postpartum period in the endogenous sensitisation assay in women, and the conditioned pain modulation assay failed to produce analgesia in either group. Postpartum women, however, reported less intense pain than controls at the end of topical capsaicin exposure (1.3 [1.4] vs 2.0 [2.0] on 0e10 verbal scale), and acute hypersensitivity after capsaicin was less in postpartum than control rats (withdrawal threshold 25 [15] vs 3.6 [1] g). Conclusions: These results agree with a recent report that oxytocin may desensitise the transient receptor potential for vanilloid-1 channel, although other explanations, including hormone effects, are possible. These results do not, however, support the inhibition of capsaicin-evoked spinal sensitisation in the postpartum period. Clinical trial registration: NCT01843517. Editor's key pointsRecovery from Caesarean delivery in women is more rapid than expected, so the authors hypothesised that endogenous modulation of acute pain is altered postpartum.There was no effect of the postpartum period on endogenous sensitisation, but women reported less intense capsaicin-evoked pain and rats had less acute hypersensitivity after capsaicin. There was no postpartum difference in pain experience to acute phasic heat stimuli and experimentally induced hypersensitivity in new mothers who are breastfeeding, but capsaicin-evoked pain was reduced. The mechanisms of this postpartum analgesic effect are not clear, but may involve oxytocin-induced desensitisation of pain-related ion channels.

show abstract

“…All females were on hormone-based contraceptives and tested negative for pregnancy before administration of study medication. Other end-points from the study have been published previously [11][12][13][14].…”

mentioning

confidence: 99%

Genetic Influences of OPRM1,OPRD1 and COMT on Morphine Analgesia in a Multi‐Modal, Multi‐Tissue Human Experimental Pain Model

Nielsen

Christrup

Sato

et al. 2017

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol-O-methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double-blind, two-way, crossover, single-dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis-generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models.

show abstract

Modelling concentration–analgesia relationships for morphine to evaluate experimental pain models

Cited by 12 publications

References 18 publications

Pharmacokinetic models of morphine and its metabolites in neonates:

Pharmacokinetic models of morphine and its metabolites in neonates:

Capsaicin-induced pain and sensitisation in the postpartum period

Genetic Influences of OPRM1,OPRD1 and COMT on Morphine Analgesia in a Multi‐Modal, Multi‐Tissue Human Experimental Pain Model

Contact Info

Product

Resources

About