Combining Opioid Agonists and Antagonists as a Solution for Opioid-induced Constipation
Combining Opioid Agonists and Antagonists as a Solution for Opioid-induced Constipation
European Gastroenterology & Hepatology Review Volume4 Issue 2
Published: October 2009
Published: October 2009
Severe acute pain, in most instances, is effectively relieved by morphine or numerous potent semi-synthetic (oxycodone) or synthetic (fentanyl) opioids. While these drugs are also effective in the treatment of severe, chronic pain, their use is limited by their well-known side effects. One of the most frequently reported side effects is opioid-induced constipation (OIC). While many side effects occur at the beginning of pain treatment and are attenuated or even disappear over time, constipation persists or can even get worse.1 Consequently, a high proportion of patients with chronic pain receiving opioids require one or more laxative treatment.2 Even the most aggressive laxative regimens are often ineffective as they do not target the underlying mechanisms of opioid action in the gastrointestinal tract.2 Our increasing understanding of opioid pharmacology has now opened new vistas of research into methods of effectively treating pain with opioids while minimising their side effects. Such strategies include the use of fixed opioid agonist and antagonist combinations, or the use of selective peripheral antagonists as an add-on therapy to be combined with opioids on an individual basis.
Opioids and Their Receptors
Opioids are widely used for pain relief, both for short periods of acute pain (e.g. post-operatively) or over prolonged periods in patients with chronic pain, such as cancer patients. They exert their analgesic effects via the μ-opioid receptors present in the central nervous system (CNS). First discovered in the 1970s, there are now known to be three main types of opioid receptor – μ, κ and δ – which differ in their ligand-binding properties, distribution and physiological function.3 Three different subtypes of μ receptor, two subtypes of δ receptor and three subtypes of κ receptor have been discussed. Heterodimers of μ and δ receptors due to post-translational modifications have been identified.4 This contributes to greater opioid receptor variability. A large number of opioid receptor subtypes exist and there is evidence to suggest that they may act via different intracellular signalling systems in different cells. Therapeutic ligands, such as morphine, appear to be relatively non-specific, binding to all three subtypes of μ receptor. This can explain the numerous limiting side effects that morphine and other opioids exhibit, despite being very potent analgesics.
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Keywords:
Opioid Agonists, Antagonists, Opioid-induced Constipation, Constipation,
Opioid Agonists, Antagonists, Opioid-induced Constipation, Constipation,
