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Written by

Dr Michael Überall Dr Michael Überall is Vice-President of the German Pain Association (Deutsche Gesellschaft für Schmerzmedizin) and pain specialist at the Institute for Neurological Sciences (IFNAP), Nürnberg, Germany

Chronic pain and the role of opioids in pain management

Published 28 October 2015

The successful control and relief of chronic pain should be based on an understanding of the neurophysiological mechanisms and pathways involved and the role of opioids in pharmacological management is important, explains Dr Michael Überall

Key learning points

  • Risk of developing chronic pain is based on personal predisposition, environmental factors and psychological factors.
  • Understanding the neurophysiological mechanisms involved in chronic pain may help clinicians develop individualised treatment plans.
  • As part of the biopsychosocial approach to the management of chronic pain, focus should be on understanding the neurophysiological mechanisms of pain and the effects on social functioning and psychological factors.
  • Pharmacology is still the basis for the necessary pain relief when managing chronic pain.

Although there is no formal definition of chronic pain, it is generally considered to be recurrent or continuous pain, which has no apparent biological value, is unresponsive to standard analgesic medication and has persisted for at least three to six months.1,2 Chronic pain is a common condition among the general population, with approximately 12– 30% of the adult population in Europe currently affected by moderate-to-severe chronic pain.3,4

The risk of developing chronic pain, or the ‘chronification’ of pain, and hence an individual’s response to pain, will vary depending on several fundamental factors.5,6 These have been identified as:

  • Personal predisposition, which may be influenced by factors such as gender, age and the efficiency of the endogenous inhibitory system;
  • Environmental factors such as external stresses, a previous history of pain, obesity, smoking and poor sleep; and
  • Psychological factors such as anxiety and depression.5,6

Consequently, successful treatment of chronic pain needs to be based on an understanding of the mechanisms involved, as well as identifying suitable goals and selecting appropriate treatment for individual patients.5

The role of opioids in the treatment of chronic pain has substantially increased over recent years.3,4,7 The short-term use of opioids for the treatment of chronic non-cancer pain is now recognised as potentially beneficial over some other treatments, whilst evidence supporting their long-term use in chronic non-cancer pain is comparatively lacking.7

Pain, the brain and opioids

Understanding the neurophysiological mechanisms involved in the development and maintenance of chronic pain is fundamental to helping clinicians develop effective, individualised treatment plans.5 The pain experience is modulated by the dynamic interaction of ascending and descending pathways and the neural mechanisms involved, both peripherally (vascular, mechanical, thermal or chemical lesions affecting the nerve) and centrally (spinal or supraspinal hyperactivity).5,8 Therefore, chronic pain is related either to the hyperactivity of nociceptive signalling (ascending) or, on the other hand, to the hypoactivity of endogenous pain inhibitory mechanisms (descending) throughout the CNS.5

Activation of opioid receptors expressed at various central and peripheral sites results in an analgesic effect by either inhibiting the ascending pathway or, conversely, activating the descending pathway.9,10 However, the unpredictability of the therapeutic effect of CNS drugs in individual patients makes the process of drug development in this area both slow and expensive.11 Functional magnetic resonance imaging (fMRI), a non-invasive imaging technique that can complement molecular imaging, has recently been used to help provide a better understanding of the therapeutic mechanisms of drugs and to identify clinically relevant biological markers of efficacy.11,12

Studies using imaging techniques such as fMRI have identified that cognitive factors, such as the anticipation of pain or the expectation of pain relief, are capable of modulating the site-specific activation of opioid receptor signalling in the human brain.13–15 This confirms that the experience of chronic pain arises from psychological, as well as physiological, factors.13–15

These findings have helped to shed light on drug effects that are specific to distinct components of nociceptive processing or the experience of pain.13 They may provide a greater long-term understanding as to how treatments unfold over time, such as drug combinations with mechanisms of action involving both central agonist activity as well as peripheral antagonist activity on mu-opioid receptors,16 and how these interact with the subjective pain experience.13

The patient-centric perspective of pain

As already outlined, the activation of pain involves both physiological and psychological influences.13–15 Because of this, a biopsychosocial approach to pain is now widely accepted as the best evidence-based approach to chronic pain management.17 With this in mind, pain management needs to focus not only on understanding the neurophysiological mechanisms of pain, but also its effects on social functioning and psychological factors.17

Although it is unclear as to whether it is the physical or emotional aspect of pain which influences health-related quality-of-life, it is certain that chronic pain is often associated with a greater impairment of quality-of-life.18 Chronic pain can affect the ability to work and maintain activities of daily living, in addition to causing emotional distress, depression and personality changes, which all affect social well-being.19

Consequently, non-pharmacological methods such as self-management strategies have been shown to be essential in optimising health outcomes for those with chronic pain.20 Nevertheless, pharmacology is still the basis for the necessary pain relief when managing chronic pain;5 although there may be considerable variation in patient responses to analgesia, both in terms of efficacy and side-effects.21

The adverse effects of opioids are well documented and opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use.22–25 Approximately 40% of patients receiving opioids for chronic non-cancer pain report fewer than three bowel movements per week.26,27 The gastrointestinal symptoms associated with opioid use add to the burden already experienced by chronic pain patients, negatively impacting quality-of-life and, in some cases, affecting opioid treatment itself.27

PROBE study of oxycodone/naloxone

Prolonged release oral oxycodone/naloxone (Targin®*) is indicated for the treatment of severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation (OIC) by blocking the action of oxycodone at opioid receptors locally in the gut.28

A recent prospective, randomised, open-label, blinded endpoint (PROBE), streamlined study compared the overall safety profile and tolerability of oxycodone/naloxone with that of traditional opioid therapy, namely oxycodone or morphine, in 88 centres in the German healthcare system.29,30 A total of 453 patients requiring WHO step III opioids to treat low back pain were randomised (1:1:1) to receive oxycodone/naloxone (112.9±34.2mg mean morphine equivalent per day [MEQ]), oxycodone (106.6±37.4mg MEQ) or morphine (103.8±39.3mg MEQ), for a period of three months.30

The primary endpoint of this study was the percentage of responders at the end of the study compared with baseline. Responders had to fulfil all the following criteria:29

  • Complete the 12-week treatment period without any treatment emergent adverse event leading to study discontinuation.
  • At least 50% relief with respect to pain intensity, functionality and quality of life.
  • A maximum worsening of bowel function of 50% or less (measured by the Bowel Function Index [BFI]).

At the end of the study period, there were significantly more patients taking oxycodone/naloxone who met the responder criteria for the primary endpoint, compared with oxycodone and morphine respectively (22.2%, 9.3% and 6.3%; p<0.001). Secondary outcomes also demonstrated that a greater proportion of patients receiving oxycodone/naloxone kept normal BFI scores during treatment, compared with oxycodone and morphine, respectively (86.8%, 63.6% and 53.8%; p<0.001).29

The PROBE study demonstrated that the oxycodone/naloxone combination was associated with significantly better tolerability, a lower risk of OIC and a significantly greater analgesic efficacy than oxycodone and morphine.29 This has not been seen in previous clinical trials and there is no clear explanation as to why this may be the case. It may not only be the result of fewer GI side-effects and significantly less OIC and/or better opioid absorption, one explanation might be the opioid-receptor independent activity of naloxone on nociceptive neurons.29,30


Chronic pain is a common condition among the general population that needs to be addressed from both a physiological and psychological perspective. While self-management can help address the social functioning and psychological factors associated with chronic pain, a full understanding of the neurophysiological mechanisms is needed to optimise health outcomes for people living with chronic pain.

With OIC being the most prevalent patient complaint associated with opioid use, one therapeutic development is a dual approach that targets both the pain and, at the same time, counteracts OIC. Moreover, as has been shown by the recent PROBE study, prolonged release oral oxycodone/naloxone has demonstrated superior efficacy and tolerability over some individual treatments for chronic pain.

  • Dr Michael Überall is Vice-President of the German Pain Association (Deutsche Gesellschaft für Schmerzmedizin) and pain specialist at the Institute for Neurological Sciences (IFNAP), Nürnberg, Germany

*Targin® (oxycodone/naloxone) is licensed for severe pain which can be adequately managed only with opioid analgesics. Targin® is also known as Targinact® and Targiniq® in other countries. UK prescribing information can be found via link below.


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Date of preparation: October 2015; Job bag code: MINT/PAEU-15018