Faculty Opinions recommendation of Fatal respiratory depression after multiple intravenous morphine injections.

Morphine remains widely used in clinical settings due to its potent analgesic properties. However, one of the gravest risks of all opioids is their ability to induce respiratory depression and subsequent brain hypoxia that can lead to coma and death. Due to these life-threatening effects, our goal was to examine the effects of intravenous morphine at a wide range of doses (0.1–6.4 mg/kg) on changes in brain oxygen levels in freely moving rats. We used oxygen sensors coupled with high-speed amperometry and conducted measurements in the nucleus accumbens (NAc) and subcutaneous (SC) space, the latter serving as a proxy for blood oxygen levels that depend on respiratory activity. We also examined the effects of morphine on NAc, muscle, and skin temperature. Morphine induced dose-dependent decreases in SC oxygen levels, suggesting respiratory depression, but differential effects on NAc oxygen: increases at low and moderate doses (0.1–1.6 mg/kg) and decreases at the highest dose tested (6.4 mg/kg). Morphine also increased brain temperature at low and moderate doses but induced a biphasic, down-up change at high doses. The oxygen increases appear to result from a neurovascular coupling mechanism via local vasodilation and enhanced oxygen entry into brain tissue to compensate for blood oxygen drops caused by modest respiratory depression. At high morphine doses, this adaptive mechanism is unable to compensate for the enhanced respiratory depression, resulting in brain hypoxia. Hence, morphine appears to be safe when used as an analgesic at clinically relevant doses but poses great risks at high doses, likely to be abused by drug users. NEW & NOTEWORTHY With the use of oxygen sensors coupled with amperometry, we show that morphine induces differential effects on brain oxygen levels, slightly increasing them at low doses and strongly decreasing them at high doses. In contrast, morphine dose dependently decreases oxygen levels in the SC space. Therefore, morphine engages opposing mechanisms affecting brain oxygen levels, enhancing them through neurovascular coupling at low, clinically relevant doses and decreasing them due to dramatic respiratory depression at high doses, likely to be abused.

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Fatal Respiratory Depression after??Multiple Intravenous Morphine Injections

Clinical Pharmacokinetics ◽

10.2165/00003088-200645110-00001 ◽

2006 ◽

Vol 45 (11) ◽

pp. 1051-1060 ◽

Cited By ~ 52

Author(s):

J??rn L??tsch ◽

Rafael Dudziak ◽

Rainer Freynhagen ◽

J??rgen Marschner ◽

Gerd Geisslinger

Keyword(s):

Respiratory Depression ◽

Intravenous Morphine

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Simultaneous Measurement and Integrated Analysis of Analgesia and Respiration after an Intravenous Morphine Infusion

Anesthesiology ◽

10.1097/00000542-200411000-00021 ◽

2004 ◽

Vol 101 (5) ◽

pp. 1201-1209 ◽

Cited By ~ 56

Author(s):

Albert Dahan ◽

Raymonda Romberg ◽

Luc Teppema ◽

Elise Sarton ◽

Hans Bijl ◽

...

Keyword(s):

Respiratory Depression ◽

Half Life ◽

Integrated Analysis ◽

Population Pharmacokinetic ◽

Mu Opioid ◽

Effect Site ◽

Morphine Infusion ◽

Arterial Blood ◽

Intravenous Morphine ◽

Respiratory Variables

Background To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. Methods Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. Results Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01). Conclusions Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

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