Intrathecal adenosine for treatment of acute pain : safety assessments and evaluation in experimental, surgical and labour pain

Abstract

Adenosine is an endogenous compound present in all cells in the body with a wide range of physiological effects. Exogenous administration of adenosine is used clinically as an antiarrytmic agent and as a vasodilator. In animals, antinociceptive effects have been demonstrated by adenosine and adenosine analogues, after systemic as well as intrathecal (IT) administration. In patients, a low dose of adenosine IV infusion during surgery reduces anaesthetic requirements as well as the need for postoperative analgesics. Patients with severe chronic neuropathic pain have obtained pain alleviation after both IV infusion and IT administration of adenosine. Whether adenosine can influence acute nociceptive pain in humans after IT administration is not known. Therefore, the aim of this thesis is to evaluate if adenosine can be a valuable analgesic in the treatment of acute clinical pain, in terms of both efficacy and safety.

As part of the safety evaluation, rats were injected IT with 100µg of adenosine daily for 2 weeks to study potential neurotoxic effect on the spinal cord. Light and electron microscopy as well as a quantitative morphometric evaluation were performed which did not show any signs of histological changes indicating neurotoxicological effects of adenosine. Further, the effects of a single IT injection of adenosine and of the vehicle mannitol on spinal cord blood flow (SCBF) was measured using laser Doppler flowmetry technique. SCBF increased 230% by Adenosine 50 µg and 180% by mannitol 500µg compared with saline, without any effect on systemic blood pressure. Thus, any antinociceptive effects of IT adenosine administration are not due to spinal cord ischemia.

In healthy volunteers, doses of 500-2000 µg adenosine were injected IT and pharmacological levels of adenosine were detected in cerebrospinal fluid after 20 min. Adenosine did not influence alertness or reflexes, induce motor disturbances or any other adverse effects in doses up to 1000µg. After 2000µg a transient (15min) lumbar migraine-like pain was reported. In conjunction, the efficacy of IT adenosine on different human experimental pain models was tested. IT adenosine treatment reduced the area of secondary allodynia after topical mustard oil and attenuated the decrease of tactile pain threshold within this area and attenuated tourniquet induced ischemic pain. However, pain during cold immersion was unaffected. This implies a modulatory effect on central sensitisation.

Patients planned for hysterectomy received an IT injection of 500µg adenosine or saline, randomised and double blind, before induction of anaesthesia. Perioperative requirements of anaesthetics as well as postoperative need for analgesics were assessed, but no difference was detected between treatments. In a randomised double-blind study in parturients, 500µg of adenosine + 10µg sufentanil or 10µg sufentanil was injected IT for labour pain relief. No increase in efficacy or duration of analgesia could be demonstrated.

In conclusion: IT administration of adenosine could not detect any neurotoxic effects in rats or in healthy volunteers. Further, adenosine was effective in modulating central sensitisation in human experimental pain. Even though the effect site for the pain modulating effect of adenosine is suggested to be situated at the spinal cord level, IT adenosine could not be demonstrated to reduce clinical pain in patients. The results from these studies demonstrate that acute clinical pain cannot be attenuated by IT administration of adenosine.