Codeine, heightened pain sensitivity and medication overuse headache: a neuroimmune hypothesis and novel treatment strategy.
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Date
2015
Authors
Johnson, Jacinta Lee
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Rolan, Paul Edward
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Thesis
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Abstract
Codeine is the most widely consumed opioid analgesic worldwide. It relies upon partial metabolism to morphine to elicit analgesic effects. Paradoxically, the pain-reliever morphine has previously been linked to states of increased pain sensitivity; such as medication overuse headache and opioid-induced hyperalgesia and allodynia. Despite the clinical impact of medication overuse headache the pathophysiology behind this disorder remains unclear and mechanism-based treatments are lacking. Although most acute headache treatments are alleged to cause medication overuse headache, within this thesis we conclude from the literature opioids are the drug class most strongly associated with worsening headache. In opioid-induced hyperalgesia and allodynia sensitivity to normally noxious, and non-noxious stimuli respectively, are enhanced due to opioid exposure.
Chronic morphine may exacerbate pain in the long-term by non-specifically activating toll-like receptor-4 (TLR4) on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Here we hypothesise medication overuse headache is a specific form of opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation and glial priming, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation and subsequent neuroinflammation. The first part of this thesis examines the efficacy of a glial-attenuating treatment, ibudilast, in the clinical management of medication overuse headache induced by opioid use in a double-blind, randomised, placebo-controlled parallel group study. Patients received ibudilast 40 mg twice daily or placebo for I weeks and recorded headache and analgesic intake using a headache diary for 4-weeks prior to randomisation and throughout the treatment phase. No reduction in headache burden, opioid analgesic intake or headache related quality of life were observed in the ibudilast group compared to placebo, however, valuable safety data were obtained demonstrating ibudilast 80 mg/day is well tolerated, facilitating the use of similarly high doses in future studies for alternative indications. Prior to this PhD project the relationship between codeine and increased pain sensitivity had not been investigated. ln silico docking simulations performed as part of this PhD suggest codeine binds to MD2, an accessory protein forTLR4, signifying it may be able to induce hyperalgesia independent of conversion to morphine. Evidence that codeine can induce hyperalgesia would sit in line with our glial hypothesis for opioid overuse headache. Thus, the second part of this PhD includes a series of preclinical experiments to 1.) determine if chronic codeine alters pain sensitivity 2) ascertain if pre-existing glial activation primes for opioid-induced hyperalgesia, 3) investigate signalling pathways involved and 4) assess potential interventions to reverse exacerbated pain sensitivity. Hyperalgesia and allodynia were measured using hot plate and von Frey tests respectively, at baseline, day 3 and day 5 in mice receiving intraperitoneal codeine 2t mg/kg, morphine 20 mg/kg or saline, twice daily. Our preclinical studies demonstrate that despite providing lesser acute analgesia, equimolar codeine and morphine induced similar hot plate hyperalgesia, suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity, emphasising the non-opioid receptor-dependent nature of this phenomenon. lL-RA reversed codeine-induced hyperalgesia and allodynia, and knock-out of TLR4 protected against codeine-induced pain sensitivity changes. Glial attenuation with ibudilast reversed codeine-induced allodynia and thus could be investigated as potential treatment for conditions involving codeine-induced pain enhancement.
School/Discipline
School of Medical Sciences
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2015
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This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.