Correspondence

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American Journal of Emergency Medicine

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American Journal of Emergency Medicine 34 (2016) 746-755

Morphine in the setting of acute myocardial infarction: pros and cons?

To the Editor,

Acute myocardial infarction (AMI) commonly seen in outpatient emergency care can lead to high hospitalization and high mortality, characterized by sudden onset of myocardial ischemia. The latest guide- lines for clinical practice recommend the therapeutic principles for is- chemia relief to prevent severe adverse consequences, such as death, cardiogenic shock, heart failure, or reinfarction. In general, chest pain is the unique complaint of patients with AMI, and the Symptom severity varies widely resulting from not only personal emotions but multiple factors breaking the balance of oxygen Supply and demands while the myocardium is at risk [1-3]. Pain itself in turn deteriorates the myocar- dial ischemia for the sympathetic activation, which can increase the workload of the heart [2]. Despite the lack of rigorous studies designed to assess the effect of morphine administration in patients with AMI, clinical practice guidelines for managing patients with ST-segment ele- vation myocardial infarction (STEMI) strongly recommend morphine as a routine medicine for analgesia [4,5]. Likewise, the European Society of Cardiology guidelines for managing STEMI patients recommend intra- venous opioids (eg, morphine) to relieve pains (class I indication; a Level of evidence C) [5]. Meanwhile, Antiplatelet agents of pharmacolog- ical therapy are of considerable significance in treating patients with acute coronary syndrome, including STEMI. Given that several drugs are usually administrated together in the acute setting, the drug-to- Drug interaction may be inevitable.

In clinical trials, the use of adenosine diphosphate inhibitors seems beneficial to patients presenting with myocardial infarction [6-8], but we probably neglected that there are short of morphine administration in these randomized controlled trials. Which has been recommended for routine use in patients with myocardial ischemia suffering chest pain [9]. Different from all expectations, it has been reported that the use of morphine is related to higher mortality in patients with non- ST-segment elevation acute coronary syndromes [10], probably because of the influence on pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers, which may result in treatment failure in susceptible individuals [11]. In addition, coadministration of mor- phine moderately lowers the concentration of ticagrelor and its active metabolite AR-C124910XX [12] but does not inhibit its pharmacody- namic effect on healthy volunteers within 6 hours after drug use [11]. Here may exist a biologically plausible cause-effect relationship where- in opiates inhibit gastric motion and emptying, which will attenuate the absorption of the orally administrated drugs as well as decrease its peak plasma concentration [13]. Consequently, its efficacy will be affected.

? Conflicts of interest: none declared.Financial disclosures: none declared.

So far, opioids have become highly effective drugs for relieving pain since its isolation from a plant benefited the insomnia treatment as a pharmacologically active ingredient in 1805 [14]. The effect of morphine on physiology is associated with activated opioid receptors, which can cause Drug dependence, drug addiction, drug abuse, or withdrawal syn- drome. Therefore, it is called opioid analgesics, narcotic analgesics, or ad- dictive analgesics. As we know, opioid analgesics relieve pain by mimicking the function of a variety of endogenous opioid peptides (?- endorphin, dynorphin A and B, and endomorphin I and II), which could invoke a series of special membrane receptors by generating re- lated signals, thus activating endogenous pain-modulating systems. There are 3 classes of opioid receptors for the reported effects of the opi- oid: u(u1, u2), ?(?1, ?2), and q(q1, q2, q3), and the related genes are MOR, DOR, and KOR, respectively. They are all linked through G- proteins to depress adenylate cyclase and then activate receptor-gated potassium channels and inhibit Voltage-gated calcium channels, which results in interfering with neurotransmitter release and disturbing noci- ceptive transmission. u-Receptors have been thought to be the main part of these receptors producing analgesic effects of opioids and several Major adverse events occurring in the brain and in the gastrointestinal tract [15]. After the injection of morphine, it can activate these receptors after combining with them. u-Receptors in brain take charge of analge- sia, sedation, euphoria, and respiratory depression, the last of which is an adverse effect leading to hypoventilation and then hypoxemia so that myocardial ischemia could be deteriorated [2]. However, in terms of the cardiovascular system, morphine has no significant influence on heart rate and heart rhythm, but morphine in higher doses can dilate vessels and lead to an inconvenient adverse effect in AMI patients that peripheral resistance is reduced [16]. Therefore, we should bear in mind that the principle of morphine use is to use the lowest effective dose because of the fewest adverse effects. Perhaps, it is better to take repeated low-dose therapy. It is noted that naloxone (0.1-0.2 mg intra- venously per 15 minutes), an opioid receptor antagonist, can immedi- ately reverse the adverse function of morphine administration [2]. In addition, such morphine drugs could protect patients with AMI from myocardial ischemia injury like ischemic preconditioning and decrease the infarction lesions in patients suffering AMI. The physiological mech- anism may be associated with ?1 receptors which can activate K_ATP channels of mitochondria. Importantly, morphine slows gastric peristal- sis and suppresses the secretion of digestive glands, including intestinal and pancreatic secretions, leading to delayed drug absorption. More- over, nausea, vomiting, and constipation are also common adverse ef- fects of morphine used in patients with AMI. Usually, u-receptors may be thought to play an irreplaceable role here [15].

What matters the most in patients with AMI is the drug-to-drug in-

teractions between morphine and P2Y₁₂ receptor inhibitors or anti- platelet drugs. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) registry including 57,093 patients with non- ST-segment elevation acute coronary syndromes treated with

0735-6757/(C) 2016

Correspondence / American Journal of Emergency Medicine 34 (2016) 746-755

morphine alone or with nitroglycerin and clopidogrel together showed

747

Seung-Woon Rha, MD, PHD

that patients treated with morphine had a higher adjusted risk of death than those without morphine [10]. The negative effect of morphine on AMI patients may be caused by drug-to-drug interaction. The prodrug clopidogrel takes 2 steps to be converted to its active metabolite by cy- tochrome P450 enzymes [17], which may provide more time for drug- to-drug interactions, especially in patients with impaired clopidogrel metabolism. Median values of C_max and area under the curve of clopidogrel active metabolite decreased in the following order: rapid N extensive N intermediate N poor metabolizers. Morphine causes a “poor metabolizer phenotype” in individuals genetically prone to exten- sively metabolize clopidogrel [18], leading to decreasing the concentra- tions and pharmacodynamic effects of clopidogrel. Morphine can delay the absorption of clopidogrel and lower the serum concentration of its active metabolite, whereas it can raise the residual platelet reactivity [18]. However, a study enrolling 24 healthy volunteers treated with morphine and ticagrelor showed that morphine could slightly decrease ticagrelor plasma concentrations rather than inhibit its pharmacody- namic effects within 6 hours after drug administration [11] for a not long follow-up period. Nevertheless, these selected subjects do not con- cern patients with AMI. So small is the sample size that there undoubt- edly exist a few of subjective and objective biases, and thus, a large randomized controlled trial is wanted. Ticagrelor is not metabolized through the liver [12], which leads to a sudden onset of effect and less variability in response among patients [19,20]. Kubica et al [21] assessed the influence of infused morphine on pharmacokinetics and pharmaco- dynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with AMI and concluded that morphine could delay and attenuate ticagrelor exposure and effect in patients with AMI. Platelet reactivity was higher in AMI patients with ticagrelor and morphine than those receiving placebo within the first 6 hours after drug use [21]. High platelet reactivity is a predictive increased risk factor of ischemic outcomes [22].

In addition, guidelines also recommend that the administration of injected beta-blockers and nitrates in patients with ongoing ischemia (chest pain) needs to be considered without contraindication [2]. If chest pain persists after intravenous beta-blockers, standard doses of morphine use relieve pain better than increased dosages of metoprolol [23]. Moreover, other Analgesic drugs, like nonsteroidal anti- inflammatory drugs and cyclooxygenase-2 inhibitors, are contraindi- cated in AMI patients because of increased risk of death and adverse outcomes assessed by several epidemiological studies and retrospective analyses of randomized related trials [4]. Besides, benzodiazepines have shown to be efficient anxiolytics over a long period of time in terms of pain relief and positive Cardiovascular effects; however, clinical trials are not adequate [24,25]. Researchers also recommend some possible strategies to overcome or at least diminish the adverse influence on oral P2Y₁₂ receptor inhibitors in AMI patients, including cangrelor, con- comitant use of a GP IIb/IIIa receptor inhibitor, a prokinetic agent (metoclopramide), crushed ticagrelor tablets for sudden absorption, and replacement of morphine by a short-acting analgesic such as alfentanil [26,27]. However, these strategies and their effects or interac- tions in AMI patients need to be assessed in future studies.

Given that the above observations indicate that comprehensive evaluation of the pros and cons of morphine administration for managing AMI patients may have great impact on treatment, reperfu- sion success, and long-term prognosis, large prospective, randomized clinical trials or cohort studies regarding this tissue are urgently warranted.

Nixiao Zhang, BS Kangyin Chen, MD, PHD

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease Department of Cardiology, Tianjin Institute of Cardiology Second Hospital of Tianjin Medical University, Tianjin, 300211

People’s Republic of China

Cardiovascular Center, Korea University Guro Hospital, Seoul, 152-703, Korea

Guangping Li, MD, PHD Tong Liu, MD, PHD

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease Department of Cardiology, Tianjin Institute of Cardiology Second Hospital of Tianjin Medical University, Tianjin, 300211

People’s Republic of China

Corresponding author. Tianjin Key Laboratory of Ionic-Molecular

Function of Cardiovascular Disease Department of Cardiology Tianjin Institute of Cardiology

Second Hospital of Tianjin Medical University No. 23 Pingjiang Rd, Hexi District, Tianjin, 300211

People’s Republic of China Tel.: +86 22 88328648; fax: +86 22 28261158

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2016.01.016

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6. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, et al. Addition of clopidogrel to aspirin and Fibrinolytic therapy for myocardial infarc- tion with ST-segment elevation. N Engl J Med 2005;352:1179-89.
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   Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a ran- domized trial in healthy volunteers. Eur J Clin Invest 2015.

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11. Thomas M, Malmcrona R, Fillmore S, Shillingford J. Haemodynamic effects of mor- phine in patients with acute myocardial infarction. Br Heart J 1965;27:863-75.
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    Kohli P, Wallentin L, Reyes E, Horrow J, Husted S, Angiolillo DJ, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation 2013;127:673-80.

15. Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 2015.
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18. Huffman JC, Stern TA. The use of benzodiazepines in the treatment of chest pain: a review of the literature. J Emerg Med 2003;25:427-37.
19. Ellingsrud C, Agewall S. Morphine in the treatment of acute pulmonary oedema-why? Int J Cardiol 2015;202:870-3.
20. Kubica J, Kozinski M, Navarese EP, Tantry U, Kubica A, Siller-Matula JM, et al. Cangrelor: an emerging therapeutic option for patients with coronary artery disease. Curr Med Res Opin 2014;30:813-28.
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    Anaphylaxis-triggered Takotsubo syndrome:

    

    What is its prevalence??

    To the Editor,

    I read with interest the study by Cha et all [1], published online ahead of print on October 3, 2015 in the Journal, based on a retrospective review of 300 patients with anaphylaxis of various etiologies (AN), who present- ed to the Emergency Department (ED) and were evaluated for myocardial injury (MYIN), with troponin I, and transthoracic echocardiogram (ECHO) within 5 h of presentation. The authors detected 22 patients with MYIN (7.3%), 4 of whom showed regional wall motion abnormalities (RWMA), with 3 of 4 also presenting with reduced systolic function. Of these 4 patients, 1 showed reverse Takotsubo syndrome (TTS), 2 patients had RWMA discordant to the distribution of coronary arteries, and 1 patient showed RWMA of the inferior wall, with electrocardiogram ST-segment elevation in leads II, III, and aVF. All these 4 patients were discharged after they had recovered from their cardiomyopathy without any specific intervention required. A total of 12 patients among the 22 with MYIN showed ischemic electrocardiogram changes. ECHO was performed on 15 of the 22 patients with MYIN, and ECHO follow-up was done only in 1 of the 4 patients with RWMA. Eleven of the 22 patients with MYIN received epinephrine (EPI). All in all the authors did an admirable job in securing relevant data in the retrospective assessment of a large population presenting in the ED.

    The authors refer to MYIN and “AN-induced cardiomyopathy in AN” to characterize the subgroup of the 22 patients with MYIN and/or ECHO-derived diagnosis of reduced systolic function and/or RWMA [1]. Pathophysiologically the authors have attributed the MYIN and/or the AN-induced cardiomyopathy in their 22 patients to Kounis syn- drome and the mediated Coronary vasospasm [1], and to TTS, at least in 1 of their patient. The authors also refer to the previous literature on TTS and its association with AN and/or administration of EPI [1].

    The authors are cognizant of the limitations of their study and pro- pose that “further prospective studies are required to investigate serum catecholamines, serial troponin I, ECHO, and prognosis of MYIN in patients with AN [1]. In reference to TTS, it is conceivable that it remains one of the most under-recognized conditions. Indeed work carried out prospectively in intensive care units, using proactive assess- ment with serial ECHO, have disclosed the emergence of TTS in a large

    ? Conflicts of interest: Nothing to disclose.

    proportion of the patients cared for in the intensive care unit [2,3]. Also TTS was more frequently detected, that expected, in patients with post-Aneurysmal subarachnoid hemorrhage, when serial ECHO was car- ried out prospectively [4]. In addition, if one liberalizes his/her views of what constitutes a case of TTS, to include milder or atypical variants of this syndrome [5], more cases of TTS will be detected in the patients ad- mitted via the ED in the heels of AN due to foods, drugs, insect stings, with EPI administration inducing even more cases. Currently we do not know the true prevalence of AN-triggered TTS, and thus the authors’ proposal to evaluate this issue prospectively is welcome.

    John E. Madias, MD Icahn School of Medicine at Mount Sinai, New York, NY Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY

    Division of Cardiology, Elmhurst Hospital Center, 79-01 Broadway

    Elmhurst, NY, 11373 Tel.: +1 718 334 5005; fax: +1 718 334 5990

    E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2016.01.022

    References

    Cha YS, Kim H, Bang MH, Kim OH, Kim HI, Cha K, et al. Evaluation of myocardial injury through serum troponin I and echocardiography in anaphylaxis. Am J Emerg Med 2016;34:140-4. http://dx.doi.org/10.1016/j.ajem.2015.09.038.

22. Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH, et al. Left ventricular apical bal- looning due to severe physical stress in patients admitted to the medical ICU. Chest 2005;128:296-302.
23. Yang HS, Kim HJ, Shim HJ, Kim SJ, Hur M, Di Somma S, et al. Soluble ST2 and tro- ponin I combination: useful biomarker for predicting development of stress car- diomyopathy in patients admitted to the medical intensive care unit. Heart Lung 2015;44:282-8.
24. Abd TT, Hayek S, Cheng JW, Samuels OB, Wittstein IS, Lerakis S. Incidence and clinical

    characteristics of takotsubo cardiomyopathy post-aneurysmal subarachnoid hemor- rhage. Int J Cardiol 2014;176:1362-4.

    Madias JE. Forme fruste cases of Takotsubo syndrome: a hypothesis. Eur J Intern Med

    2014;25, e47.

    Analysis of prescription patterns in opioid deaths shows startling findings

    

    Re: Lev R, Lee O, Petro S, Lucas J, Castillo EM, Vilke GM, Coyne CJ. Who is prescribing controlled medications to patients who die of prescription drug abuse? Am J Emerg Med. 2016 Jan.;34(1):30-5

    To the Editor,

    A retrospective observational study investigating San Diego Medical Examiner reports of prescription drug-related deaths that occurred in San Diego County during 2013 assessed the prescription controlled medication patterns in patients dying of prescription drug abuse [1]. This article, assessing prescription patterns including number of pills by specialty, provides important information. Primary care physicians are significantly involved with long-term opioid prescribing, measured at 39.1% of all prescriptions, whereas physician assistants and nurse practitioners prescribe 8.9% of the total. Pain physicians contributed to 4.2% of the prescriptions, and when pain physicians, physical medicine and rehabilitation physicians, and anesthesiologists are combined, they represent 9.5% of all total prescriptions. These findings are similar to those published about methadone deaths [2]. Therefore, this article confirms Centers for Medicare and Medicaid Services data that the ma- jority of Opioid prescriptions are from specialties other than pain