Clinical studies in patients with persistent pain: towards optimisation of pharmacological treatment

Haji Mohd Zin, Che S. (2008). Clinical studies in patients with persistent pain: towards optimisation of pharmacological treatment PhD Thesis, School of Pharmacy, The University of Queensland.

       
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Author Haji Mohd Zin, Che S.
Thesis Title Clinical studies in patients with persistent pain: towards optimisation of pharmacological treatment
School, Centre or Institute School of Pharmacy
Institution The University of Queensland
Publication date 2008-07
Thesis type PhD Thesis
Supervisor Dr Lisa Nissen
Professor Maree Smith
Dr Brendan Moore
Total pages 249
Total colour pages 62
Total black and white pages 187
Language eng
Subjects 320000 Medical and Health Sciences
Formatted abstract Chronic pain can be nociceptive, inflammatory, neuropathic or a combination of these types of
pain. Post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) are two of the most
common types of neuropathic pain. A number of drugs including tricyclic antidepressants,
gabapentin, pregabalin, oxycodone, and topical lidocaine are available for the treatment of
neuropathic pain. However, when each is used as monotherapy, these drugs provide pain relief in
40-60% of patients, leaving the rest with unremitting pain.
Within the past fifteen years, there has been increasing evidence that cytokines produced by nonneuronal
cells in the central nervous system (CNS) such as activated glia, may play a key role in
the establishment and/or maintenance of chronic pain. Pro-inflammatory cytokines such as the
interleukins, IL-1H and IL-6, appear to exacerbate pain while anti-inflammatory cytokines such as
IL-10 appear to ameliorate pain. In the past five years, the potential role of cytokines in
compromising the analgesic effects of opioids, has been recognized. Hence, it has been proposed
that receptors and ion channels on activated glial cells in the CNS may provide novel targets for
the development of new therapeutic agents for the relief of chronic pain in humans. In addition,
an improved understanding of their ability to modulate opioid analgesia has the potential to
improve the clinical utility of opioid analgesics in the management of chronic pain.
My doctoral research program was undertaken in an attempt to generate new knowledge that may
have the potential to improve outcomes in the management of chronic pain in patients. Part One
of my research evaluated the efficacy and tolerability of a fixed low daily dose of oxycodone at
10 mg/day in combination with pregabalin (75-600 mg/day) in 62 patients with PHN or PDN.
The results from this six week randomized, double-blind, placebo-controlled, parallel group study
demonstrated that irrespective of whether patients received a combination of
pregabalin/oxycodone or pregabalin/placebo, they reported a significant improvement in their
levels of pain at the end of the study. This study further supports the effectiveness of pregabalin
in the treatment of PHN/PDN, but does not support the notion that the addition of a low dose
oxycodone 10 mg/day enhances the pregabalin effect.Part Two of my research program was a preliminary investigation of the plasma and
cerebrospinal fluid (CSF) concentrations of cytokines in patients with chronic non-cancer pain
who had received intrathecal (i.t.) opioid therapy of morphine or hydromorphone administered
alone or in combination with local anaesthetics. The aim of Part A of this cytokine study was to
examine whether or not there was a significant correlation between the plasma and CSF
concentrations of each of the pro-inflammatory cytokine, IL-6, and the anti-inflammatory
cytokine, IL-10, in paired samples of these fluids collected from 50 patients who were already
receiving i.t. opioids for chronic pain management. The paired blood and CSF samples collected
during a pump refill. The results showed that there was no significant correlation between paired
plasma and CSF concentrations of either IL-6 or IL-10 (p > 0.05), consistent with the notion that
cytokines produced by peripheral immune cells do not readily cross the blood-brain-barrier and
that cytokines in the CNS are produced by activated glia.
Part B of this latter study was designed to evaluate a possible temporal effect of chronic use of i.t.
opioids on the concentrations of the pro-inflammatory cytokine, IL-6, and the anti-inflammatory
cytokine, IL-10, in paired plasma and CSF samples collected from 10 patients, who were
scheduled to start using i.t. opioids and who were assessed over a three month period. The plasma
and CSF samples were taken just prior to i.t. pump implantation, at 4 to 7 days after i.t. pump
implantation and initiation of a chronic i.t. opioid infusion, and at three months after initiation of
the chronic i.t. opioid infusion. These preliminary results demonstrated that chronic i.t. opioid
administration appears to upregulate CSF concentrations of the pro-inflammatory cytokine, IL-6,
which in turn may contribute to the attenuation of opioid analgesia and subsequently to the
development of tolerance and hyperalgesia after chronic use of opioids. Future studies beyond the
scope of the present investigation are required to further investigate this notion.
The outcomes from Part One and Two of my doctoral research program provide a significant
contribution to the knowledge base for the management of chronic pain. The randomized
controlled trial suggests a potential for lower doses of pregabalin 75 and 150 mg/day in
combination with a low fixed daily dose of oxycodone at 10 mg/day to be used for the treatment
of neuropathic pain. This subsequently would be more cost effective and would reduce the
healthcare utilization of pregabalin in the treatment of neuropathic pain, but larger clinical trialsconducted over a longer timeframe are required to further evaluate this proposition. The results
from Part Two of this study show that evidence from animal studies implicating a role for
cytokines in the establishment and maintenance of persistent pain as well as modulating the
effects of opioids appear to translate to humans with persistent pain, but additional research is
required. Together my doctoral research findings provide important information in the quest to
improve the clinical management of chronic pain and to improve the clinical utility of analgesics
drugs.
Keyword Neuropathic pain
post-herpetic neuralgia
painful diabetic neuropathy,
pregabalin
oxycodone

 
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Created: Thu, 13 Nov 2008, 20:01:28 EST by Ms Che Haji Mohd Zin on behalf of School of Pharmacy