Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery

Dale, Ola; Thoner, J; Nilsen, Turid; Tveita, T.; Borchgrevink, Petter C.; Klepstad, Pål

doi:10.1007/s00228-007-0329-x

Cited by 16 publications

(9 citation statements)

References 19 publications

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“…This may explain our finding regarding the lack of correlation between M6G plasma concentrations and morphine clinical effects in the PACU. Interestingly, after intravenous administration of 10 mg of morphine, no metabolites were detected in CSF samples after 120 min despite their rapid rise in plasma concentrations, confirming the lack of contribution of M6G to morphine-related central nervous effects during this period [37]. Our finding is in line with the failure to produce analgesia in experimental and clinical pain after administration of M6G at similar doses to those resulting from metabolism of analgesic doses of morphine [36][37][38][39].…”

Section: Discussionsupporting

confidence: 82%

“…Interestingly, after intravenous administration of 10 mg of morphine, no metabolites were detected in CSF samples after 120 min despite their rapid rise in plasma concentrations, confirming the lack of contribution of M6G to morphine‐related central nervous effects during this period [37]. Our finding is in line with the failure to produce analgesia in experimental and clinical pain after administration of M6G at similar doses to those resulting from metabolism of analgesic doses of morphine [36–39]. It may be noted that another recent study in postoperative patients demonstrated the delayed role of M6G on morphine analgesia, with a significant correlation between M6G/M3G plasma concentration ratio and analgesia observed only after the fourth hour of intravenous morphine administration [40].…”

Section: Discussionmentioning

confidence: 91%

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Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period

Hammoud

Aymard

Lechat

et al. 2010

Fundamental &Amp; Clinical Pharmacology

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Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 91%

Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period

Hammoud

Aymard

Lechat

et al. 2010

Fundamental &Amp; Clinical Pharmacology

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“…IV morphine has a more rapid and extensive initial effect compared with IM, which is supported by the findings of the pharmacokinetic study by Dale et al 80 Dale compared the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after IV and IM administration of morphine 10 mg after surgery. The uptake of morphine to the CSF was consistently higher after IV administration than after IM administration.…”

Section: Resultsmentioning

confidence: 75%

The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection

Jin¹,

Zhu²,

Chen³

et al. 2015

PPA

131

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BackgroundIntravenous (IV), intramuscular (IM), and subcutaneous (SC) are the three most frequently used injection routes in medication administration. Comparative studies of SC versus IV, IM versus IV, or IM versus SC have been sporadically conducted, and some new findings are completely different from the dosage recommendation as described in prescribing information. However, clinicians may still be ignorant of such new evidence-based findings when choosing treatment methods.MethodsA literature search was performed using PubMed, MEDLINE, and Web of Sciences™ Core Collection to analyze the advantages and disadvantages of SC, IV, and IM administration in head-to-head comparative studies.Results“SC better than IV” involves trastuzumab, rituximab, antitumor necrosis factor medications, bortezomib, amifostine, recombinant human granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, recombinant interleukin-2, immunoglobulin, epoetin alfa, heparin, and opioids. “IV better than SC” involves ketamine, vitamin K1, and abatacept. With respect to insulin and ketamine, whether IV has advantages over SC is determined by specific clinical circumstances. “IM better than IV” involves epinephrine, hepatitis B immu-noglobulin, pegaspargase, and some antibiotics. “IV better than IM” involves ketamine, morphine, and antivenom. “IM better than SC” involves epinephrine. “SC better than IM” involves interferon-beta-1a, methotrexate, human chorionic gonadotropin, hepatitis B immunoglobulin, hydrocortisone, and morphine. Safety, efficacy, patient preference, and pharmacoeconomics are four principles governing the choice of injection route. Safety and efficacy must be the preferred principles to be considered (eg, epinephrine should be given intramuscularly during an episode of systemic anaphylaxis). If the safety and efficacy of two injection routes are equivalent, clinicians should consider more about patient preference and pharmacoeconomics because patient preference will ensure optimal treatment adherence and ultimately improve patient experience or satisfaction, while pharmacoeconomic concern will help alleviate nurse shortages and reduce overall health care costs. Besides the principles, the following detailed factors might affect the decision: patient characteristics-related factors (body mass index, age, sex, medical status [eg, renal impairment, comorbidities], personal attitudes toward safety and convenience, past experience, perception of current disease status, health literacy, and socioeconomic status), medication administration-related factors (anatomical site of injection, dose, frequency, formulation characteristics, administration time, indication, flexibility in the route of administration), and health care staff/institution-related factors (knowledge, human resources).ConclusionThis updated review of findings of comparative studies of different injection routes will enrich the knowledge of safe, efficacious, economic, and patient preference-oriented medication administration as well as...

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“…In humans, ~44–55% of morphine is metabolized to morphine-3-glucuronide (M3G), 9–15% to morphine-6-glucuronide (M6G), 8–10% excreted as morphine and the remainder converted into numerous minor metabolites (Christrup, 1997; Andersen et al, 2003). Clinical studies have consistently found M3G and M6G in the CNS following systemic morphine, including in lumbosacral cerebrospinal fluid (CSF) (Sjogren et al, 1998; Dale et al, 2007). …”

mentioning

confidence: 99%

Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β

et al. 2010

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Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine. M3G has little-to-no affinity for opioid receptors and induces pain by unknown mechanisms. The pain-enhancing effects of M3G have been proposed to significantly and progressively oppose morphine analgesia as metabolism ensues. We have recently documented that morphine activates toll-like receptor-4 (TLR4), beyond its classical actions on μ-opioid receptors. This suggests that M3G may similarly activate TLR4. This activation could provide a novel mechanism for M3G-mediated pain enhancement, as (a) TLR4 is predominantly expressed by microglia in spinal cord and (b) TLR4 activation releases pain-enhancing substances, including interleukin-1 (IL1). We present in vitro evidence that M3G activates TLR4, an effect blocked by TLR4 inhibitors, and that M3G activates microglia to produce IL1. In vivo, intrathecal M3G (0.75 μg) induced potent allodynia and hyperalgesia, blocked or reversed by interleukin-1 receptor antagonist, minocycline (microglial inhibitor), and (+)-and (−)-naloxone. This latter study extends our prior demonstrations that TLR4 signaling is inhibited by naloxone nonstereoselectively. These results with (+)-and (−)-naloxone also demonstrate that the effects cannot be accounted for by actions at classical, stereoselective opioid receptors. Hyperalgesia (allodynia was not tested) and in vitro M3G-induced TLR4 signaling were both blocked by 17-DMAG, an inhibitor of heat shock protein 90 (HSP90) that can contribute to TLR4 signaling. Providing further evidence of proinflammatory activation, M3G upregulated TLR4 and CD11b (microglial/macrophage activation marker) mRNAs in dorsal spinal cord as well as IL1 protein in the lumbosacral cerebrospinal fluid. Finally, in silico and in vivo data support that the glucuronic acid moiety is capable of inducing TLR4/MD-2 activation and enhanced pain. These data provide the first evidence for a TLR4 and IL1 mediated component to M3G-induced effects, likely of at least microglial origin.

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Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery

Cited by 16 publications

References 19 publications

Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period

Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period

The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection

Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1β

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