The attractiveness of opposites:

 agonists and antagonists

Published 6 October 2014

Professor Tony O’Brien explains the seemingly counter-intuitive approach of co-prescribing an agonist and an antagonist

Key learning points

• Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management.
• The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management.
• The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation.

Introduction

The undertreatment of both cancer and non-cancer pain is well documented.^1,2 The individual, societal and economic consequences are profound. Uncontrolled pain is associated with a variety of negative impacts across a range of QoL domains, including physical, cognitive, emotional and behavioural functions.^3–5 The Declaration of Montreal recognises that pain management is inadequate in most of the world and asserts that access to pain management is a fundamental human right.⁶ Whilst pain management requires a multidimensional approach, in many instances the skilled use of opioid medications is essential.^7,8
In 1973, a number of research groups demonstrated the existence of stereospecific opiate binding sites in the CNS.^9–11 In 1976, Martin et al demonstrated the existence of a number of opioid receptor subtypes.¹² Opioid receptors are found throughout the nervous system including the brain, spinal cord and peripheral nerves.¹³ In addition, opioid receptors are found in the gut¹⁴ and opioid-induced bowel dysfunction results from the activation of mu-receptors in the enteric nervous system, resulting in uncoordinated and dysfunctional propulsion, increased fluid absorption and reduced secretion of water and electrolytes into the bowel lumen.^15,16 Because the entire gut expresses opioid receptors, the effects of opioids are not confined to the large bowel. Opioid use is associated with dry mouth, oesophageal dysmotility, delayed gastric emptying, increased pyloric tone, delayed transit times, a decrease in the secretion of water and electrolytes into the intestinal lumen, a net increase in the absorption of luminal fluid and an increase in resting anal sphincter pressure.^17,18
Opioid-induced bowel dysfunction is a major limiting factor in the use of opioids in pain management. Constipation and associated bowel symptoms occur in up to 90% of patients taking opioid medications and, not surprisingly, constipation is described as the most common and bothersome GI side-effect reported by patients taking opioid medications.^18–20 The UK’s National Institute for Health and Care Excellence guideline CG140 advises clinicians to inform patients that ‘constipation affects nearly all patients receiving strong opioid treatment’ and recommends laxative prescription for all patients initiating strong opioids.²⁰ However, the evidence supporting the use of standard laxative medications, with or without associated lifestyle changes and dietary modifications, is weak.^21,22 A Cochrane database systematic review on the management of constipation in palliative care patients was carried out in 2010 (and published in 2011).²³ The 2010 update of the first review, published in 2006, found ‘evidence on laxatives for management of constipation remains limited due to insufficient RCTs’.²³ However, the conclusions of the 2010 update differed from the initial review such that it found that the administration of the opioid antagonist methylnaltrexone (administered subcutaneously) was effective in ‘inducing laxation in palliative care patients with opioid-induced constipation [OIC] and where conventional laxatives have failed.’²³

The goal of therapy is to enable a person to live a fuller and more meaningful life; clinicians are not treating pain or opioid receptors – they are treating the person
©Fuse/Thinkstock

Agonist with an antagonist – a counter-intuitive approach?

The co-prescription of an agonist and an antagonist seems almost counter-intuitive. Medical students and junior doctors quickly learn that naloxone is a powerful opioid antagonist and as such, it seems strange to want to use it with an opioid agonist. Oxycodone is a semi-synthetic thebaine derivative that has been in clinical use since 1917.²⁴ It became commercially available as a single agent in 1981. In 1996, it was launched as a sustained-release formulation.²⁴ The analgesic potency of oral oxycodone relative to oral morphine is in the order of 1.5:1 to 2:1.²⁵ Oxycodone has a relatively high oral bioavailability of up to 87%.^25,26
The availability of an oral, long-acting formulation of oxycodone and naloxone in a fixed 2:1 ratio represents a significant development in our therapeutic options when managing severe pain.²⁷ The strengths currently available in Ireland are 5mg/2.5mg, 10mg/5mg, 20mg/10mg and 40mg/20mg.²⁸ It is important to remember that this formulation is a WHO step III opioid and the effects of the antagonist component (naloxone) are limited to the gut. This compartmentalisation of effect ensures that central analgesia is maintained and the risk of opioid withdrawal is avoided. The oxycodone dose in the combination product is bioequivalent to the same dose administered as a single agent.²⁹
Once ingested, both the oxycodone and naloxone progress along the gut in the normal fashion and the rate of their release into the gut lumen is determined by the characteristics of the sustained release formulation.²⁹ Within the gut, the naloxone will bind preferentially to the mu-opioid receptors because of its greater affinity.¹⁵ Thus, the agonist oxycodone is largely prevented from binding to opioid receptors in the gut, thereby conferring a degree of protection from the more usual intestinal opioid-associated adverse effects. In time, both the oxycodone and naloxone are absorbed and transported via the portal system to the liver. Within the liver, the naloxone is extensively metabolised by glucuronidation, such that 97–98% of the naloxone is metabolised in the first pass.²⁸ Negligible amounts of naloxone reach the systemic circulation, thus preserving central analgesia.
The liver plays a vital function in the metabolism and clearance of most opioids.³⁰ Patients with impaired liver function will have increased plasma concentrations of both oxycodone and naloxone compared with normal healthy subjects. However, the levels of naloxone are proportionately higher than the oxycodone in such circumstances. Thus, caution must be exercised when using the combination product in patients with mild hepatic dysfunction and in those deemed at risk of developing hepatic dysfunction. This combination product is contraindicated in patients with moderate or severe hepatic dysfunction. Normal vigilance is advised when using this product in the elderly and in patients with renal impairment.²⁸ Plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment.²⁸ Naloxone concentrations are affected to a higher degree than oxycodone.²⁸

Efficacy and safety profile evidence

In 2008, Vondrackova et al evaluated the safety profile and efficacy of oxycodone in combination with naloxone in a prolonged release formulation in a population of 463 patients with chronic non-malignant pain.³¹ The analgesic efficacy of the combination formulation was comparable to single agent prolonged release oxycodone and additionally, an improvement in OIC was observed.³¹ Simpson et al (2008) studied a population of 322 adult patients with non-cancer pain requiring opioid therapy.³² The fixed-ratio combination of oxycodone and naloxone offered patients effective analgesia whilst significantly improving OIC, compared with prolonged release oxycodone alone.³² In a study by Meissner et al, 202 patients with mainly non-cancer pain under stable oral oxycodone therapy were randomised to receive naloxone or placebo.³³ The study demonstrated a significant improvement in OIC in those patients on the oxycodone/naloxone combination compared with those on single agent oxycodone, with maintenance of analgesic efficacy.³³ The 2:1 oxycodone/naloxone ratio was identified as the most suitable for further development. Bowel function was assessed using the Bowel Function Index (BFI) in all studies.^31–33
Ahmedzai et al (2012) studied a group of 185 patients with chronic cancer pain.³⁴ The combination product of oxycodone and naloxone provided a significant improvement in OIC, as measured by the BFI, compared with oxycodone alone, without compromising analgesic efficacy or safety.

Conclusion

This approach, using an established and familiar step III opioid (oxycodone) in combination with an opioid antagonist (naloxone) in a fixed-dose ratio prolonged release oral formulation, offers the prospect of predictable and reliable analgesia with a significant reduction in the burden of OIC.

• Professor Tony O’Brien is a consultant physician in palliative medicine at Marymount University Hospital & Hospice/Cork University Hospital, Ireland and at the College of Medicine and Health, University College, Cork, Ireland

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