The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man

In this thesis, a series of related studies on opioids are reported. In epidemiological studies of opioid overdose it is shown that opioid overdose has increased 14 times more than other overdoses in Edinburgh in the past 4 decades. I also discussed the predisposing factors for overdose. I developed...

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Main Author: Afshari, Reza
Published: University of Edinburgh 2006
Online Access:http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.735426
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description In this thesis, a series of related studies on opioids are reported. In epidemiological studies of opioid overdose it is shown that opioid overdose has increased 14 times more than other overdoses in Edinburgh in the past 4 decades. I also discussed the predisposing factors for overdose. I developed and calculated a series of toxicity indices for opioids in Scotland, and used hospital discharge data, poisons information statistics (telephone enquiries/TOXBASE accesses) and prescription data to calculate fatality indices (FTI) and minimise the effects of confounders on the traditional FTI which uses only prescription volume as the denominator. I used an identical methodology to relate non-fatal consequences of overdose to prescriptions and proposed toxic morbidity indices (TMIs). I suggest an integrated approach by using both FTIs and TMIs as new methods for toxico-vigilance. Using this methodology I demonstrated that co-proxamol has a10 times excess risk of fatality in comparison to co-codamol and co-dydramol, while TMIs are similar. This demonstrates the inherent toxicity of the drug in overdose, and led, in part, to withdrawal of this drug in the UK. Further I showed in patients that QRS duration is prolonged in co-proxamol overdose, an effect which was dose dependent, suggesting sodium channel blockade as a potential cause of its excess mortality in overdose. I showed from mortality statistics that dihydrocodeine appears safer than methadone. I also estimated diamorphine illicit availability from overdose rates in Edinburgh. I introduced a comparison of mortality from single agent in comparison to multiple agent overdose (MSDPR) as a measure of risk from cointoxications. I showed that diamorphine, morphine and codeine are significantly more dangerous in co-intoxication than other opioids. Studies on the cardiovascular effects of opioids in overdose and in volunteers were then performed. It has been suggested previously that therapeutic doses morphine have no effects on the cardiovascular system in man in the supine position. I first showed acute depressor effects of dihydrocodeine and methadone overdose on peripheral systolic, diastolic, pulse, and aortic and end systolic pressures, and 02 saturation in dihydrocodeine overdose in comparison to a parallel control group. I was able to exclude any effect on arterial stiffness. I showed that 02 saturation under 95% is a marker of haemodynamic depressant effects of dihydrocodeine. Later in a controlled trial in healthy volunteers, I verified the cardiovascular depressor effects of intravenous morphine in doses to a maximum of 16 mg. These effects were not dose dependent. There was also no relationship to change in reaction time, and no major change in plasma concentrations of histamine or catecholamines. Lower 02 saturation, and higher end tidal volume C02 potentially contributed to the haemodynamic effects. I showed that intra venous morphine decreased aortic and peripheral systolic, diastolic, mean, pulse, end systolic, and sitting systolic pressures, while heart rate increased. A number of other indices, stroke index, systemic vascular resistance, ventricular ejection time, peak flow index, ejection ratio, end diastolic index, index of contractibility and acceleration index also decreased. Overall these findings indicate that at these doses morphine decreased afterload, was negatively inotropic, positively chronotropic, had no effect on cardiac work, while maintaining left ventricular performance. In a second study I found that these effects in general were not antagonised by naloxone. Using occlusion plethysmograph and intra arteriolar morphine infusion, I further showed the existence of a peripheral action of morphine on arteries, at higher concentrations 0.6 to 3 microgram/ml, which was dose dependent. Weal, flare and itching also developed rapidly and were dose dependant. Tachyphylaxis to these effects did not develop. By using pre treatment with antihistamines and measurement of plasma histamine I showed that histamine was the prime mediator for both arteriolar and skin effects. The peripheral site of action is likely to be mediated via mast cell release of histamine from arteriolar surrounding supporting tissues, and this effect influences vascular tone in man. The arteriolar effects were antagonised by LNMMA, indicating that nitric oxide release is probably caused by histamine. High concentrations of morphine induce anaphylactoid reactions. The novel observations in this thesis explain this phenomenon and may clarify the pathophysiology of opioid-induced non-cardiac pulmonary oedema, and anaphylactoid reactions. If fluid shifts occur elsewhere in the body this may contribute to hypovolemia in shock, since endogenous opioids are thought to have a role in this situation. These findings suggest that Hi and H2 blockers should be studied in the management of patients with opioid-induced non-cardiac pulmonary oedema, and those receiving high doses of morphine such as in surgery and acute pain. The effects of Ht and H2 blockers in opioid overdose should also be investigated.
author Afshari, Reza
spellingShingle Afshari, Reza
The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
author_facet Afshari, Reza
author_sort Afshari, Reza
title The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
title_short The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
title_full The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
title_fullStr The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
title_full_unstemmed The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
title_sort cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man
publisher University of Edinburgh
publishDate 2006
url http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.735426
work_keys_str_mv AT afsharireza thecardiovasculareffectsofopioidanalgesicsstudiesontheroleofopioidandnonopioidreceptorsinman
AT afsharireza cardiovasculareffectsofopioidanalgesicsstudiesontheroleofopioidandnonopioidreceptorsinman
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spelling ndltd-bl.uk-oai-ethos.bl.uk-7354262018-05-12T03:18:06ZThe cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in manAfshari, Reza2006In this thesis, a series of related studies on opioids are reported. In epidemiological studies of opioid overdose it is shown that opioid overdose has increased 14 times more than other overdoses in Edinburgh in the past 4 decades. I also discussed the predisposing factors for overdose. I developed and calculated a series of toxicity indices for opioids in Scotland, and used hospital discharge data, poisons information statistics (telephone enquiries/TOXBASE accesses) and prescription data to calculate fatality indices (FTI) and minimise the effects of confounders on the traditional FTI which uses only prescription volume as the denominator. I used an identical methodology to relate non-fatal consequences of overdose to prescriptions and proposed toxic morbidity indices (TMIs). I suggest an integrated approach by using both FTIs and TMIs as new methods for toxico-vigilance. Using this methodology I demonstrated that co-proxamol has a10 times excess risk of fatality in comparison to co-codamol and co-dydramol, while TMIs are similar. This demonstrates the inherent toxicity of the drug in overdose, and led, in part, to withdrawal of this drug in the UK. Further I showed in patients that QRS duration is prolonged in co-proxamol overdose, an effect which was dose dependent, suggesting sodium channel blockade as a potential cause of its excess mortality in overdose. I showed from mortality statistics that dihydrocodeine appears safer than methadone. I also estimated diamorphine illicit availability from overdose rates in Edinburgh. I introduced a comparison of mortality from single agent in comparison to multiple agent overdose (MSDPR) as a measure of risk from cointoxications. I showed that diamorphine, morphine and codeine are significantly more dangerous in co-intoxication than other opioids. Studies on the cardiovascular effects of opioids in overdose and in volunteers were then performed. It has been suggested previously that therapeutic doses morphine have no effects on the cardiovascular system in man in the supine position. I first showed acute depressor effects of dihydrocodeine and methadone overdose on peripheral systolic, diastolic, pulse, and aortic and end systolic pressures, and 02 saturation in dihydrocodeine overdose in comparison to a parallel control group. I was able to exclude any effect on arterial stiffness. I showed that 02 saturation under 95% is a marker of haemodynamic depressant effects of dihydrocodeine. Later in a controlled trial in healthy volunteers, I verified the cardiovascular depressor effects of intravenous morphine in doses to a maximum of 16 mg. These effects were not dose dependent. There was also no relationship to change in reaction time, and no major change in plasma concentrations of histamine or catecholamines. Lower 02 saturation, and higher end tidal volume C02 potentially contributed to the haemodynamic effects. I showed that intra venous morphine decreased aortic and peripheral systolic, diastolic, mean, pulse, end systolic, and sitting systolic pressures, while heart rate increased. A number of other indices, stroke index, systemic vascular resistance, ventricular ejection time, peak flow index, ejection ratio, end diastolic index, index of contractibility and acceleration index also decreased. Overall these findings indicate that at these doses morphine decreased afterload, was negatively inotropic, positively chronotropic, had no effect on cardiac work, while maintaining left ventricular performance. In a second study I found that these effects in general were not antagonised by naloxone. Using occlusion plethysmograph and intra arteriolar morphine infusion, I further showed the existence of a peripheral action of morphine on arteries, at higher concentrations 0.6 to 3 microgram/ml, which was dose dependent. Weal, flare and itching also developed rapidly and were dose dependant. Tachyphylaxis to these effects did not develop. By using pre treatment with antihistamines and measurement of plasma histamine I showed that histamine was the prime mediator for both arteriolar and skin effects. The peripheral site of action is likely to be mediated via mast cell release of histamine from arteriolar surrounding supporting tissues, and this effect influences vascular tone in man. The arteriolar effects were antagonised by LNMMA, indicating that nitric oxide release is probably caused by histamine. High concentrations of morphine induce anaphylactoid reactions. The novel observations in this thesis explain this phenomenon and may clarify the pathophysiology of opioid-induced non-cardiac pulmonary oedema, and anaphylactoid reactions. If fluid shifts occur elsewhere in the body this may contribute to hypovolemia in shock, since endogenous opioids are thought to have a role in this situation. These findings suggest that Hi and H2 blockers should be studied in the management of patients with opioid-induced non-cardiac pulmonary oedema, and those receiving high doses of morphine such as in surgery and acute pain. The effects of Ht and H2 blockers in opioid overdose should also be investigated.University of Edinburghhttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.735426http://hdl.handle.net/1842/28232Electronic Thesis or Dissertation