The oral-to-intravenous equianalgesic ratio of morphine based on plasma concentrations of morphine and metabolites in advanced cancer patients receiving chronic morphine treatment

Takahashi, Masahiko; Ohara, Takeshi; Yamanaka, Hidetoshi; Shimada, Akira; Nakaho, Toshimichi; Yamamuro, Makoto

doi:10.1191/0269216303pm824oa

Cited by 27 publications

(11 citation statements)

References 23 publications

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“…Consequently, analgesic concentrations predicted by the simulation of between 10.1 and 14.1 μg.L −1 or 14.1 and 17.6 μg.L −1 will have similar effect (i.e., that associated with effective analgesia, 10–20 μg.L −1 ). This observation, determined by simulation (Table 1), aligns with clinical equianalgesic estimates that range from 1:2.5 to as high as 1:6 20‐23 . Morphine relative bioavailability is a better pharmacokinetic parameter to use for dose estimation than the clinical measure of equianalgesia dependent on route of administration.…”

Section: Modeling Morphine Oral Bioavailability and Its Relationship ...supporting

confidence: 66%

Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Morse

Anderson

Gastine

et al. 2022

Pediatric Anesthesia

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Pharmacokinetic-pharmacodynamic modeling and simulation can facilitate understanding and prediction of exposure-response relationships in children with acute or chronic pain. The pharmacokinetics of diamorphine (diacetylmorphine, heroin), a strong opioid, remain poorly quantified in children and dose is often guided by clinical acumen. This tutorial demonstrates how a model to describe intranasal and intravenous diamorphine pharmacokinetics can be fashioned from a model for diamorphine disposition in adults and a model describing morphine disposition in children.Allometric scaling and maturation models were applied to clearances and volumes to account for differences in size and age between children and adults. The utility of modeling and simulation to gain insight into the analgesic exposure-response relationship is demonstrated. The model explains reported observations, can be used for interrogation, interpolated to determine equianalgesia and inform future clinical studies. Simulation was used to illustrate how diamorphine is rapidly metabolized to morphine via its active metabolite 6-monoacetylmorphine, which mediates an early dopaminergic response accountable for early euphoria. Morphine formation is then responsible for the slower, prolonged analgesic response. Time-concentration profiles of diamorphine and its metabolites reflected disposition changes with age and were used to describe intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg.kg −1 was similar to that after intranasal diamorphine 5 mg in adults. A target concentration of morphine 30 μg.L −1 can be achieved by a diamorphine intravenous infusion in neonates 14 μg. kg −1 .h −1 , in a 5-year-old child 42 μg.kg −1 .h −1 and in an 15 year-old-adolescent 33 μg. kg −1 .h −1 .

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Section: Modeling Morphine Oral Bioavailability and Its Relationship ...supporting

confidence: 66%

Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Morse

Anderson

Gastine

et al. 2022

Pediatric Anesthesia

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“…These range between 20 and 50%. 9,[22][23][24][25] Equianalgesic doses compare the analgesic effect of an opioid substance, with regards to a comparable analgesia reached by morphine dosing (Table 3). 9,23,[26][27][28][29] Analgesia offered by intravenous diamorphine was estimated 200% that of the same dose of intravenous morphine.…”

Section: Resultsmentioning

confidence: 99%

“…Table 2 lists literature sources for the conversion between intravenous and oral morphine. These range between 20% and 50% 9 22–25. Equianalgesic doses compare the analgesic effect of an opioid substance, with regards to a comparable analgesia reached by morphine dosing (table 3).…”

Section: Resultsmentioning

confidence: 99%

“…38 Equianalgesia ranges from 1:2.5 to as high as 1:6 in adults. [22][23][24][25] This is because empiric studies have shown that a concentration range (10-20 mcg.L -1 ) has analgesic effect 39 and equianalgesia can be achieved over a range of concentrations that are attained by a range of doses. The effectiveness of breakthrough equianalgesic doses can be further complicated by the development of tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Morphine, for example has a relative bioavailability in adults of 23.9% after oral solution and 18.7% after a buccal tablet37; a relative bioavailability of 30% is reported for elixir in children 38. Equianalgesia ranges from 1:2.5 to as high as 1:6 in adults 22–25. This is because empiric studies have shown that a concentration range (10–20 mcg/L) has analgesic effect39 and equianalgesia can be achieved over a range of concentrations that are attained by a range of doses.…”

Section: Discussionmentioning

confidence: 99%

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Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

Gastine

Morse

Leung

et al. 2022

BMJ Support Palliat Care

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BackgroundIntranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation.AimTo determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics.DesignA systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed.Review sourcesPubMed (1960–2020); EMBASE (1980–2020); IPA (1973–2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration.ResultsThe systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4–88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites.ConclusionsWe estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4–13 years.

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Opioid dose titration for cancer pain

Mercadante

2023

European Journal of Pain

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BackgroundOpioid dose titration is a fundamental process of opioid therapy in cancer pain.AimsTo assess data opioid dose titration.MethodsThe principal opioid dose titration methods, outcomes, and modalities of administration regarding the different opioid preparations were examined in different clinical contexts.ResultsMost studies suggested that opioid‐naive patients should be started at doses of 15–30 mg/day of oral morphine equivalents. Opioid‐tolerant patients may receive low or higher doses of oral morphine equivalents, depending on the level of opioid tolerance. Generally, dose increments of 30%–50% seem to be indicated to start dose titration. Some patients with severe excruciating cancer pain may present as an emergency requiring a rapid application of powerful analgesic strategies. The intravenous use of opioids may circumvent this problem providing a faster pain relief, due to the large availability and rapid achievement of effective plasma concentrations.DiscussionOpioid dose titration is a delicate passage in patients with cancer pain. This approach may be different according to different clinical conditions. Opioid dose titration requires expertise to optimize cancer pain management while minimizing the development of adverse effects.ConclusionWhile most approaches are meaningful and partially supported by existing literature, more studies are necessary to establish advantages and disadvantages in different clinical conditions. Optimization of opioid dose titration is of paramount importance.SignificanceThis review provides the most recent insights on the different modalities of opioid dose titration in cancer pain management.

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The oral-to-intravenous equianalgesic ratio of morphine based on plasma concentrations of morphine and metabolites in advanced cancer patients receiving chronic morphine treatment

Cited by 27 publications

References 23 publications

Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

Opioid dose titration for cancer pain

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