2024 Volume 49 Issue 6 Pages 269-279
Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.
Congestive heart failure is a syndrome characterized by a decrease in overall cardiac function, in which cardiac output becomes insufficient to maintain adequate tissue and organ perfusion. With the progression of pathology of the heart failure, dyspnea often persists despite its optimal therapy, which severely worsens their quality of life (Kawaguchi et al., 2020). For such a difficult situation as in the advanced heart failure patients, potent analgesic morphine has been used for treating refractory dyspnea as palliative care to improve their quality of life (Kawaguchi et al., 2020; Schumacher et al., 2021). European and Japanese heart failure guidelines recommend morphine therapy for refractory dyspnea in advanced heart failure patients (Anzai et al., 2021; McDonagh et al., 2021), which may offer hope for refractory dyspnea in advanced heart failure patients like in cancer patients. However, real-world data on morphine administration for refractory dyspnea in non-cancer diseases including heart failure are still limited (Kawaguchi et al., 2020; Nakamura et al., 2023). More importantly, the cardiovascular actions of morphine by themselves have not been well characterized due to the limited role of opioid receptors in the regulation of cardiovascular system (Johnson et al., 2002; Pugsley, 2002; McDonagh et al., 2021). Specifically stating, while some effects of morphine on the cardiovascular system may be mediated by activation of peripheral opioid receptors, others can result from receptor-independent action that could not be reversed by opioid receptor antagonists (Pugsley, 2002). Accordingly, clinical as well as basic information of morphine on cardiovascular adverse effects remains limited including its potential risk toward cardiohemodynamic collapse and/or torsade de points that can help to estimate its safety margin in those patients with heart failure.
In order to start making up for the lack of information, in this study, we simultaneously assessed the cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs which can mimic the drug-induced cardiovascular responses in healthy human subjects (Sugiyama, 2008). Cardiac safety profile of morphine was evaluated in particular detail by measuring the aortic blood pressure, left ventricular pressure, cardiac output, electrocardiogram, His bundle electrogram, monophasic action potential (MAP) and ventricular effective refractory period (VERP) as well as the early repolarization period (J-Tpeak), late repolarization period (Tpeak-Tend) (Johannesen et al., 2014) and terminal repolarization period (Sugiyama, 2008). The early repolarization period serves as an indicator of net balance between inward currents (INa,L and ICa,L) and outward currents (IKs and IKr) during phase 2 of the action potential. Prolongation of this period can lead to myocardial Ca2+ overload, governing the "trigger" of premature ventricular contractions by increasing the short-term variability of ventricular repolarization (Goto et al., 2023; Kambayashi et al., 2024; Suzuki et al., 2023). Meanwhile, the late repolarization period can be used to predict the degree of IKr inhibition. Prolongation of this period may indicate a global increase in transmural dispersion of ventricular repolarization, which provides "substrate" for the initiation of spiral reentry (Johannesen et al., 2014). Furthermore, the terminal repolarization period is determined by the difference between the MAP duration and the VERP at the same site. This period reflects the magnitude of local electrical vulnerability, which provides "substrate" for the perpetuation of spiral reentry (Sugiyama and Hashimoto, 2002). Our findings revealed several new and intriguing in vivo actions of morphine.
All experiments were approved by the Toho University Animal Care and User Committee (No.19-52-395) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Toho University. Experiments were performed with female beagle dogs weighing 9.8 ± 0.4 kg (n=4), which were obtained from Kitayama Labes Co., Ltd. (Nagano, Japan). Dogs were initially anesthetized with thiopental sodium (30 mg/kg, i.v.). After intubation, anesthesia was maintained by halothane inhalation (1.0-2.0% v/v) vaporized in oxygen with a volume-limited ventilator (SN-480-3; Shinano Manufacturing Co., Ltd., Tokyo, Japan). Tidal volume and respiratory rate were set at 20 mL/kg and 15 breaths/min, respectively.
Cardiohemodynamic variablesFour clinically available catheter-sheath sets (Terumo Corporation, Tokyo, Japan) were used; two were inserted into the right and left femoral arteries toward abdominal aorta, and two were done into the right and left femoral vein toward inferior vena cava, respectively. Heparin calcium (100 IU/kg) was administered through a flush line of the catheter sheath placed at the right femoral vein to prevent the blood clotting. A pig-tail catheter was placed at the left ventricle to measure the left ventricular pressure through the right femoral artery, whereas the aortic blood pressure was measured at a space between inside of the catheter sheath and outside of the pig-tail catheter through a flush line. A thermodilution catheter (132F5; Edwards Lifesciences, Irvine, CA, USA) was positioned at right side of the heart through the right femoral vein. The cardiac output was measured with a standard thermodilution method by using a cardiac output computer (MFC-1100; Nihon Kohden Corporation, Tokyo, Japan). The total peripheral vascular resistance was calculated as total peripheral vascular resistance=mean blood pressure/cardiac output.
Electrophysiological variablesThe lead II electrocardiogram was obtained from the limb electrodes. The PR interval, QRS width and QT interval along with the J-Tpeak and Tpeak-Tend intervals were measured. The QT interval was corrected with Van de Water’s formula: QTcV=QT−0.087×(RR−1,000) with RR given in ms (Van de Water et al., 1989), whereas the J-Tpeak was corrected with Johannesen's formula: J-Tpeakc=J-Tpeak/RR0.58 with RR given in seconds (Johannesen et al., 2014).
A standard 6 French quad-polar electrodes catheter (Cordis-Webster Inc., Baldwin Park, CA, USA) was positioned at the non-coronary cusp of the aortic valve through the left femoral artery to obtain the His bundle electrogram. A MAP recording/pacing combination catheter (1675P; EP Technologies, Inc., Sunnyvale, CA, USA) was positioned at endocardium of the right ventricle through the left femoral vein to obtain MAP signals. The signals were amplified with a DC preamplifier (model 300; EP Technologies, Inc.). The MAP duration (ms) at 90% repolarization level was defined as MAP90.
The ventricle was electrically driven using a cardiac stimulator (SEC-3102; Nihon Kohden Corporation). The stimulation pulses were rectangular in shape 1-2 V of amplitude (about twice the threshold voltage) and of 1-ms duration. The MAP90 was measured during sinus rhythm (MAP90(sinus)) and at pacing cycle lengths of 400 ms (MAP90(CL400)) and 300 ms (MAP90(CL300)). The VERP was assessed with programed electrical stimuli on the right ventricle. The pacing protocol consisted of 5 beats of basal stimuli in a cycle length of 400 ms (VERP(CL400)) followed by an extra stimulus of various coupling intervals. The duration of terminal repolarization period of the ventricle was calculated by the difference between the MAP90(CL400) and VERP(CL400) at the same site.
Experimental protocolThe aortic and left ventricular pressures, electrocardiogram, His-bundle electrogram and MAP signals were monitored with a polygraph system (RM-6000; Nihon Kohden Corporation), which were analyzed with a real-time, fully automatic data analysis system (WinVAS3 ver. 1.1R24; Physio-Tech Co., Ltd., Tokyo, Japan). Each measurement of cardiohemodynamic, electrocardiographic and MAP variables as well as atrio-His (AH) and His-ventricular (HV) intervals adopted the mean of three recordings of consecutive complexes. After the basal assessment, morphine hydrochloride hydrate in a low dose of 0.1 mg/kg was intravenously administered over 10 min, and each variable was assessed at 5, 10, 15, 20 and 30 min after the start of infusion. Then, morphine hydrochloride hydrate in a middle dose of 1 mg/kg was intravenously administered over 10 min, and each variable was assessed in the same manner. Finally, morphine hydrochloride hydrate in a high dose of 10 mg/kg was intravenously administered over 10 min, and each variable was assessed at 5, 10, 15, 20, 30 and 60 min after the start of infusion.
Plasma drug concentrationBlood was sampled from left femoral artery before and 5, 10, 15 and 30 min after the start of low and middle doses infusion, and 5, 10, 15, 30 and 60 min after the start of high dose infusion. The blood samples were centrifuged at 1,500 g for 15 min at 4°C to obtain their plasma, which were stored at −80°C until the drug concentration was measured. The plasma concentration of morphine was quantified by liquid chromatography-tandem mass spectrometry system (Applied Biosystems Sciex, Framingham, MA, USA). The analytical method and representative chromatograms were provided in supplementary data.
DrugsThe following drugs were purchased: morphine hydrochloride hydrate (Morphine hydrochloride injection "DAIICHI SANKYO", Daiichi Sankyo Co., Ltd., Tokyo, Japan), thiopental sodium (Ravonal® 0.5 g for Injection, Mitsubishi Tanabe Pharma Co., Osaka, Japan), halothane (Fluothane®, Takeda Pharmaceutical Co., Ltd., Osaka, Japan) and heparin calcium (Caprocin®, Sawai Pharmaceutical Co., Ltd., Osaka, Japan).
Statistical analysisData are presented as mean ± S.E. Differences within a parameter were evaluated with one-way, repeated-measures analysis of variance (ANOVA) followed by Fisher’s LSD test as a post-hoc test for mean values comparison. A p value <0.05 was considered to be significant.
The low as well as middle dose did not induce cardiohemodynamic collapse or lethal ventricular arrhythmias in any of the animals (n=4). However, in the first experiment the high dose markedly decreased the systolic aortic blood pressure to <40 mmHg at 1.9 min after the start of infusion without showing marked electrocardiographic abnormality including ST-T morphological changes. To assist circulation of the animal, mechanically-regulated, expiratory negative airway pressure (ENAP) ventilation was started at 3 min, which has been shown to be efficacious for treating drug-induced cardiohemodynamic collapse (Hagiwara-Nagasawa et al., 2021; Goto et al., 2022). For this animal, the drug administration was continued thereafter and finished at 10 min as originally planned. The ENAP ventilation effectively increased the systolic aortic blood pressure to >40 mmHg by 60 min. The plasma concentrations of morphine were 1.0, 16.6, 2.9, 18.3 and 11.9 µg/mL at 5, 10, 15, 30 and 60 min after the start of high dose infusion, respectively. In the second experiment, the high dose also decreased the systolic aortic blood pressure to <40 mmHg at 3.3 min after the start of infusion without showing marked electrocardiographic abnormality. For this animal, the infusion of morphine was discontinued at 3.8 min. The ENAP ventilation was started at 4 min, which effectively increased the systolic aortic blood pressure to >40 mmHg by 23 min. Typical tracings of the electrocardiogram, aortic blood pressure, left ventricular pressure, and MAP signal before and 5 min after the start of high dose infusion of this animal are depicted in Fig. 1. The plasma concentrations of morphine were 4.4, 1.0, 0.8, 0.6 and 0.4 μg/mL at 5, 10, 15, 30 and 60 min after the start of high dose infusion, respectively. Both animals survived after the experimental protocol. No neurological deficit was observed in either of the 2 animals at 1 week after the experiment. As for the remaining 2 animals, the high dose infusion was not performed for the animal welfare perspective. Using the results of low and middle doses from the 4 animals, the cardiohemodynamic and electrophysiological effects of morphine were analyzed as below.
Typical tracings showing the effects of a toxic dose of morphine on the lead II surface electrocardiogram (ECG), aortic blood pressure (AoP), left ventricular pressure (LVP), and monophasic action potential signal (MAP) just before (Just before infusion: left) and 5 min after the start of infusion (5 min after the start of infusion, right). Morphine hydrochloride hydrate was infused at a speed of 1 mg/kg/min, and cardiohemodynamic collapse was induced at 3.3 min after the start of infusion (3.3 mg/kg administered). The infusion was discontinued at 3.8 min (3.8 mg/kg administered), and the mechanically-regulated, expiratory negative airway pressure ventilation was started at 4 min. As shown in the right panel, severe hypotension persisted after cessation of the drug infusion along with the shortening of PP and PR intervals, indicating reflex-mediated, increase of sympathetic tone. While marked ST-segment elevation/depression was not observed, AoP decreased greater than LVP, resulting in disappearance of pressure wave reflection component in AoP and LVP.
The time course of changes in the plasma concentrations of morphine is summarized in Fig. 2. Morphine hydrochloride hydrate in doses of 0.1 and 1 mg/kg attained the peak plasma concentrations of 0.13 ± 0.03 μg/mL (0.46 ± 0.10 μM) at 10 min and 0.97 ± 0.22 μg/mL (3.41 ± 0.77 μM) at 5 min after the start of infusion, respectively.
The time courses of changes in the plasma concentration of morphine (Plasma conc.), heart rate (HR), mean blood pressure (MBP), maximum upstroke velocity of the left ventricular pressure (LVdP/dtmax), cardiac output (CO), total peripheral vascular resistance (TPR) and left ventricular end-diastolic pressure (LVEDP) after the administration of morphine hydrochloride hydrate. Data are presented as mean ± S.E. Filled symbols represent significant differences from the corresponding pre-drug basal control values (C) by p <0.05.
The time courses of changes in cardiohemodynamic variables after the administration of low and middle doses are summarized in Fig. 2, whereas typical tracings of the aortic blood pressure and left ventricular pressure are shown in Fig. 3. The pre-drug basal control values (C) of the heart rate, mean blood pressure, maximum upstroke velocity of the left ventricular pressure, cardiac output, total peripheral vascular resistance and left ventricular end-diastolic pressure were 112 ± 11 beats/min, 100 ± 12 mmHg, 2,243 ± 365 mmHg/s, 2.9 ± 0.7 L/min, 36 ± 3 mmHg·min/L and 9 ± 2 mmHg, respectively. The low dose did not alter any of the variables. The middle dose decreased the heart rate for 15-30 min, the mean blood pressure and maximum upstroke velocity of left ventricular pressure for 10-30 min, and the total peripheral vascular resistance and left ventricular end-diastolic pressure for 5-15 min, whereas it increased the cardiac output at 5 min followed by decrease at 30 min.
Typical tracings showing the effects of 1 mg/kg of morphine hydrochloride hydrate on the lead II surface electrocardiogram (ECG), aortic blood pressure (AoP), left ventricular pressure (LVP) and monophasic action potentials (MAP) during sinus rhythm at pre-drug basal control (Control, left) and 20 min after the start of infusion (20 min after 1 mg/kg of morphine hydrochloride hydrate, right).
Typical tracings of the electrocardiogram are depicted in Fig. 3, and the time courses of changes in electrocardiographic variables after the administration of low and middle doses are summarized in Fig. 4. The pre-drug basal control values (C) of the PR interval, QRS width, QT interval and QTcV, J-Tpeakc and Tpeak-Tend were 111 ± 11 ms, 72 ± 7 ms, 295 ± 13 ms, 334 ± 12, 148 ± 17 and 116±13 ms, respectively. The low dose prolonged the QT interval for 10-15 min, whereas no significant change was detected in the other variables. The middle dose prolonged the PR interval for 20-30 min, QT interval and QTcV for 10-30 min, and Tpeak-Tend for 15-30 min, whereas no significant change was detected in the QRS width or J-Tpeakc.
Time courses of changes in the PR interval, QRS width, QT interval, QTcV, J-Tpeakc, Tpeak-Tend, and atrio-His (AH) and His-ventricular (HV) intervals; and monophasic action potential duration at 90% repolarization level during sinus rhythm (MAP90(sinus)), those at pacing cycle lengths of 400 ms (MAP90(CL400)) and 300 ms (MAP90(CL300)), ventricular effective refractory period at a basic pacing cycle length of 400 ms (VERP(CL400)), and terminal repolarization period (TRP) after the administration of morphine hydrochloride hydrate. The mean values of VERP(CL400) at 20 min, MAP90(CL400) at 30 min and terminal repolarization period for 20-30 min after the low dose administration were calculated using the results from 3 animals due to technical trouble in one animal (gray symbols). Data are presented as mean ± S.E. Filled symbols represent significant differences from the corresponding pre-drug basal control values (C) by p <0.05.
Typical tracings of the MAP are depicted in Fig. 3, and the time courses of changes in the AH and HV intervals, and MAP90(sinus) during sinus rhythm after the administration of low and middle doses are summarized in Fig. 4. The pre-drug basal control values (C) of the AH and HV intervals, and MAP90(sinus) were 90 ± 10 ms, 25 ± 1 ms and 245 ± 13 ms, respectively. The low dose did not alter any of the variables. The middle dose pro longed the AH interval for 20-30 min and the MAP90(sinus) for 15-30 min, whereas no significant change was detected in the HV interval.
Effects on the MAP90(CL400), MAP90(CL300), VERP(CL400) and terminal repolarization periodThe time courses of changes in the MAP90(CL400), MAP90(CL300), VERP(CL400) and terminal repolarization period after the administration of low and middle doses are summarized in Fig. 4. Their pre-drug basal control values (C) were 243 ± 16 ms, 217 ± 13 ms, 205 ± 4 ms and 38 ± 15 ms, respectively. In one animal, the VERP(CL400) at 20 min and MAP90(CL400) at 30 min after the low dose administration could not be recorded due to technical trouble. Thus, the mean values of VERP(CL400) at 20 min, MAP90(CL400) at 30 min and terminal repolarization period for 20-30 min after the low dose administration were calculated using the results from the other 3 animals (Fig. 4, right, gray symbols). The low dose did not alter any of the variables. The middle dose prolonged the MAP90(CL300) for 10-15 min and VERP(CL400) for 5-30 min, whereas it did not alter the MAP90(CL400) or terminal repolarization period. In addition, the increment of MAP90(sinus), MAP90(CL400) and MAP90(CL300) from their respective pre-drug control values was calculated (not shown in the figure). The increment of MAP90(sinus) was greater than the others at 20 min after the middle dose infusion, indicating a reverse frequency-dependent prolongation of repolarization phase.
Since current heart failure guidelines recommended that morphine can be used for patients having advanced heart failure with refractory dyspnea (Anzai et al., 2021; McDonagh et al., 2021), we assessed cardiohemodynamic and electrophysiological effects of morphine along with the toxicokinetic profile to clarify its safety margin using the intact beagle dogs. We found several new and interesting in vivo actions of morphine, which were analyzed as discussed below.
Rationale of drug doses and concentrationsThe recommended dose of morphine for patients having advanced heart failure with refractory dyspnea was described as 5-10 mg/day as continuous intravenous injection or subcutaneous injection (Anzai et al., 2021). Since the dose can be calculated as 0.1-0.2 mg/kg assuming the patient's weight is 50 kg, in this study we selected 0.1, 1 and 10 mg/kg to reflect clinically-relevant to supratherapeutic doses. The peak plasma concentrations of morphine were 0.13 (0.46), and 0.97 μg/mL (3.41 µM) after the administration of the low and middle doses, respectively (Fig. 2). Satisfactory analgesia in patients with cancer is reported to be associated with a broad range of steady-state plasma concentrations of 0.02-0.36 µg/mL of morphine (Neumann et al., 1982), indicating that currently administered low and middle doses provided clinically-relevant and supratherapeutic concentrations, respectively. In addition, since the plasma protein-binding ratio of morphine was reported to be 35% (Knox et al., 2024), morphine in the low and middle doses in this study could provide peak free plasma concentrations of 0.09 (0.30), and 0.63 μg/mL (2.22 µM), respectively.
Cardiohemodynamic effectsThe middle dose of morphine reduced the preload and afterload to the left ventricle, then decreased the left ventricular contractility and mean blood pressure, and finally suppressed the heart rate. The rapidly appearing arteriolar and venular dilatation may depend on morphine-induced release of histamine and prostaglandins in the vessels besides the inhibition of release of endothelium-derived contractile substance (Greenberg et al., 1994; Chen and Ashburn, 2015). Opioid receptors-dependent and/or independent mechanisms might be also involved in the vessel dilation (Pugsley, 2002). The slowly developing cardiosuppressive actions can be associated with morphine-induced inhibition of sympathetic outflow (Greenberg et al., 1994), activation of peripheral opioid receptors including κ, and receptor-independent mechanisms (Pugsley, 2002). Furthermore, morphine-induced activation of vagal afferents might have enhanced the bradycardia (Randich et al., 1991).
The high dose of morphine exerted hemodynamic collapse in 2 out of 2 animals without showing marked electrocardiographic abnormality. The magnitude of reduction of systolic aortic blood pressure was greater than that of systolic left ventricular pressure in those cases (Fig. 1 right), indicating that the rapidly appearing vasodilator action may play a more critical role than the slowly developing cardiosuppressive effects. Thus, the high dose of morphine is considered to induce distributive shock rather than cardiogenic shock, although there were some reports describing that morphine induced cardiogenic shock with reducing left ventricular ejection fraction (Feeney et al., 2011; Sein Anand et al., 2021). In addition, we used the ENAP ventilation to rescue the 2 animals showing hemodynamic collapse during the high dose infusion. Although the systolic aortic blood pressure transiently decreased to <40 mmHg, both animals survived without any neurological deficit, confirming that the ENAP ventilation is effective strategy for treating drug-induced distributive shock.
Electrophysiological effectsThe middle dose of morphine delayed the atrioventricular nodal conduction, but hardly altered the intraventricular conduction. Since morphine is known not to directly inhibit ICa (Hung et al., 1998), the negative dromotropic effect may depend on the morphine-induced release of histamine (Chen and Ashburn, 2015), activation of peripheral opioid receptors including κ, and receptor-independent mechanisms (Pugsley, 2002) in the atrioventricular node. Indeed, intra-coronary administration of histamine was shown to inhibit the atrioventricular nodal conduction (Motomura and Hashimoto, 1989). Moreover, delay in the atrioventricular nodal conduction may be associated with morphine-induced inhibition of sympathetic outflow (Greenberg et al., 1994) and/or activation of vagal afferents (Randich et al., 1991). Meanwhile, lack of change in the intraventricular conduction indicates that "morphine will not inhibit cardiac INa in the in vivo heart". The IC50 value for INa was reported to be 30 μM in rat ventricular myocytes and 25.7 μM in human atrial myocytes (Hung et al., 1998), which were 13.5 and 11.6 times higher than the peak free plasma concentration after the middle dose of morphine administration, respectively, partly supporting our hypothesis in vivo.
Although morphine has been known not to prolong the QT interval (Behzadi et al., 2018), in this study morphine prolonged the repolarization period in a reverse frequency-dependent manner besides the prolongation of Tpeak-Tend, indicating that "morphine can inhibit IKr in vivo". Meanwhile, morphine was reported to suppress IKr with IC50 values of >1 mM in human cells stably transfected with the hERG potassium channel gene (Katchman et al., 2002), which is >450 times higher than the peak free plasma concentration after the middle dose infusion of morphine, indicating that "morphine would not directly inhibit IKr in vivo". Accordingly, onset mechanisms of IKr inhibition in vivo need to be commented on. Morphine is a water-soluble substance with 1-octanol/water partition coefficient of 0.87 (Knox et al., 2024), which indicates that morphine is unlikely to accumulate in large amounts in the myocardium to directly inhibit IKr, supporting the above-mentioned hypothesis.
Opioid receptor-dependent and/or indirect effects also need to be considered. It has been reported that morphine can stimulate κ-receptor (Schumacher et al., 2021), and that κ-opioid receptor agonist may be associated with IKr inhibition (Pugsley, 2002), which may have some potential to explain the onset mechanism of QT prolongation in vivo despite a need for analysis of the exposure-response relationship. To verify this explanation and further explore alternative mechanisms of morphine-induced IKr inhibition in vivo, we analyzed the relationship between the plasma morphine concentrations and the magnitude of changes in QTcV (∆QTcV) using all data points as depicted in Fig. 5A. However, no significant correlation was found between them, indicating little possibility for opioid receptor-dependent IKr inhibition. Next, to verify the presence of hysteresis in the exposure-response relationship, a diagram showing the time course of their relationship was prepared as shown in Fig. 5B. After the low and middle doses infusion, a counterclockwise hysteresis was confirmed in the time course of relationship; namely, the ΔQTcV was further prolonged after the time point attaining Cmax. One can speculate that these findings might at least in part indicate the presence of other mechanisms like hERG trafficking inhibition (Nogawa and Kawai, 2014). Indeed, in our previous study using the same experimental protocol with the halothane anesthetized dogs (Yokoyama et al., 2009), typical trafficking inhibitor pentamidine prolonged the repolarization period in a similar time course.
The relationship between the plasma concentrations of morphine and the changes in QTcV from pre-drug basal control value (ΔQTcV) after its 0.1 (blue) and 1 mg/kg (red) administration. (A) The individual ΔQTcV values were plotted versus the plasma concentration, which was evaluated by linear regression and correlation analyses. The slope value of linear regression line was −0.4981, and the correlation r-value was −0.009201 (p=0.9575). (B) The mean ΔQTcV values at each time point after the low and middle doses administration were plotted versus the logarithmic plasma concentrations. The numbers in the symbols indicate elapsed time (min) after the start of administration of low (L, blue) and middle doses (M, red). Data are presented as mean ± S.E. Note that morphine-induced prolongation of QTcV was enhanced despite a decline in its plasma concentration.
Morphine prolonged the Tpeak-Tend (Fig. 4), which will increase the substrate for initiating the spiral reentry. Meanwhile, morphine did not prolong the J-Tpeakc, which may indicate a lack of increase in net inward current during plateau phase of action potential, suggesting that morphine will not induce myocardial Ca2+ overload leading to the onset of early afterdepolarization playing as a trigger for torsade de pointes. Moreover, morphine did not prolong the terminal repolarization period, indicating that it will not provide the substrate for perpetuating the spiral reentry. Thus, the potential of morphine to develop torsade de pointes will be small, which may partly explain lack of clinical report of torsade de pointes. However, caution should be paid on the use of morphine for patients who formerly have the trigger for the onset of TdP, including congenital long QT syndrome, chronic heart failure, concomitant use of drugs enhancing the QT-interval prolongation and/or electrolyte disturbance.
Study limitation and clinical implicationFirst, the current study was conducted in anesthetized dogs with a normal heart, which can mimic the drug-induced cardiovascular responses in healthy human subjects (Sugiyama, 2008). It needs to be elucidated using the animal models of cardiovascular disease how morphine may affect the cardiovascular system in patients having advanced heart failure with refractory dyspnea. Second, there are diverse molecular mechanisms that may be responsible for the cardiovascular action of morphine. It is necessary to examine which molecular mechanisms are primarily involved in the findings in this study.
ConclusionIntravenously administered morphine exerts a rapidly appearing vasodilator action followed by a slowly developing cardiosuppressive effects; a toxic dose of morphine would induce distributive shock rather than cardiogenic one. Morphine delayed the atrioventricular nodal conduction, but hardly altered the intraventricular conduction. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.
This study was supported in part by Japan Society of the Promotion of Sciences (JSPS KAKENNHI: Grant Number 23K08430 to AS and 23K15143 to AG) and Japan Agency for Medical Research and Development, Japan (AMED: Grant Number JP23mk0101189 to AS). The authors thank Mr. Makoto Shinozaki and Mrs. Yuri Ichikawa for their technical assistance.
Conflict of interestThe authors declare that there is no conflict of interest.
