Analgetic and algetic effects of adenosine in healthy volunteers and patients with coronary disease

Background: Adenosine is a bimodal neuromodulator with algesic and analgesic effects. The different effects of adenosine are partly due to the route of administration. Low-dose adenosine infusion induces analgesia at the same magnitude as morphine, while adenosine as bolus injection induces chest pain, similar in character as angina pectoris.

Aims: To evaluate algesic / analgesic and preconditioning effects of adenosine in patients with silent myocardial ischemia or angina pectoris and healthy volunteers and the possible gender differences and opioid effect on the adenosine-provoked pain.

Methods and results: In paper I, the tolerance to adenosine-provoked pain was tested in patients with silent myocardial ischemia, angina pectoris and healthy volunteers. Patients with silent myocardial ischemia had higher pain threshold compared to the other two groups. This difference was not modified by opioid antagonist, naloxone.

In paper II, the hemodynamic and pain response to high-dose adenosine infusion and the effects of an exogenous opioid agonist, β-endorphin and antagonist, naloxone were studied. High-dose adenosine infusion induced pain of oscillatory character which was not modulated by β-endorphin or naloxone.

In paper III, the influence of gender on adenosine-induced pain and the analgesic effect of β-endorphin were investigated. Β-endorphin induced analgesia in men but not in women. Naloxone counteracted the analgesic effect in men.

In paper IV, the preconditioning effect of low-dose adenosine infusion as pretreatment to physical exercise was studied. Adenosine improved the regional ventricular function in the ischemic walls during maximal work loud compared to placebo. No changes in ventricular function were noted in the non-ischemic walls.

In paper V, the preconditioning effect of low-dose adenosine infusion as pretreatment to ischemic pharmacological provocation and its effect on coronary flow reserve were studied. Ventricular function was improved in the ischemic wall segments during peak stress following adenosine pretreatment but not placebo, without affecting the coronary flow reserve.

Conclusions: There are some differences in tolerance to adenosine in patient with asymptomatic and symptomatic ischemic heart disease. Patients with silent myocardial ischemia have decreased sensitivity to adenosine-provoked pain, which is not modulated by naloxone. In contrast no differences are demonstrated in adenosine-provoked pain between the genders. However in males β-endorphin induces analgesia, which is counteracted by naloxone, while in females β-endorphin does not modulate the adenosine-induced pain. High-dose adenosine infusion induces chest pain, which is not continuous and has oscillatory character. The fluctuation of pain is independent of β-endorphin and naloxone. Low-dose adenosine infusion, in the dose range that induces analgesia, improves the ischemic ventricular function without any effect on coronary flow reserve, ruling out vasodilatation and unloading as the mechanisms for improved ventricular function.

List of scientific papers

I. Sadigh-Lindell B, Sylvén C, Berglund M, Eriksson BE (2003). Role of adenosine and opioid-receptor mechanisms for pain in patients with silent myocardial ischemia or angina pectoris: a double-blind, placebo-controlled study. J Cardiovasc Pharmacol. 42(6): 757-63.
https://doi.org/10.1097/00005344-200312000-00010

II. Sadigh-Lindell B, Sylvén C, Berglund M, Eriksson BE (2004). High-dose adenosine infusion provokes oscillations of chest pain without correlation to opioid modulation: A double-blind controlled study. J Pain. 5(9): 459-475.
https://doi.org/10.1016/j.jpain.2004.06.009

III. Sadigh B, Berglund M, Fillingim RB, Sheps D, Sylvén C (2006). beta-endorphin modulates adenosine provoked chest pain in men, but not in women - A comparison between patients with ischemic heart disease and healthy volunteers. Clin J Pain. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/18075400

IV. Sadigh B, Sylvén C, Berglund M, Brodin LÅ, Quintana M (2007). The preconditioning effect of low dose adenosine infusion during exercise test in patients with ischemic heart disease A double-blind, cross over, placebo controlled study. [Submitted]

V. Sadigh B, Shahgaldi K, Sylvén C, Quintana M, Winter R (2007). Pretreatment with low-dose adenosine infusion improves ischemic wall motion at pharmacological stress without affecting the myocardial perfusion in patients with coronary artery disease a double-blind, placebo controlled, cross over study. [Submitted]