Oxycodone may be more effective than morphine in treatment of visceral pain - New research suggests

Main Category: Pain / Anesthetics
Article Date: 26 Aug 2005 - 11:00 PDT

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Results of a new experimental study in healthy volunteers, presented today at the IASP 11th World Congress of Pain, suggest that the use of oxycodone, an established, modern synthetic opioid compound, may be better at treating visceral pain than morphine, the previously established gold standard within this therapy area.

The results, consistent with clinical experience, show for the first time significant differences between oxycodone and morphine in the treatment of visceral pain, suggesting the compound may be used as a treatment for this type of pain.

Today's paineurope newswire provides an overview of the debilitating condition of visceral pain, the study team's rationale for carrying out the research and a discussion with regards to the significance of the results in clinical practice.

What is visceral pain?

Visceral pain, the pain felt when internal organs, such as the heart, lungs, gut, bladder and uterus, are damaged or injured, is the most common form of pain and can range in severity from mild discomfort to agony.

Whilst the exact prevalence of visceral pain is difficult to determine, diseases such as gastro-oesophageal reflux disease and irritable bowel syndrome - where visceral pain is the predominant symptom - affect up to 20 per cent of the population in the western world. Compared with cutaneous pain, visceral pain is mostly chronic, and typically patients need treatment with analgesics.

Visceral pain may be the only symptom experienced by the patients, (for example in cardiac angina). However, in many patients, visceral pain is part of a complex syndrome involving a number of different types of pain from many organs and tissues, typical in cancer. In some patients visceral pain is thought to have a neuropathic component, such as in chronic pancreatitis. These patients suffer from disabling pain that is often related to food intake, which can lead to anorexia and complications relating to malnutrition. Visceral pain is, therefore, one of the most challenging symptoms in gastroenterology.

"Visceral pain is one of the most challenging symptoms of gastroenterology", explained Professor Lars Arendt-Nielsen, Department of Gastroenterology, Aalborg University, Denmark. "This study is the first time that analgesics have been assessed using a multi-modal, multi-tissue pain assessment approach, providing an opportunity to assess the differentiated effect of new and existing drugs on specific tissues and specific pain modalities".

An overview of human experimental pain

Human experimental pain research provides the opportunity to activate the visceral pain system in a standardised manner and to assess the evoked responses in a quantitative way. Such an experimental approach can provide a better understanding of the mechanisms involved in visceral pain transduction, transmission and perception under normal and pathophysiological conditions. Human experimental pain research bridges the gap between basic animal studies and clinical applications. It also provides better characterisation of visceral pain mechanisms in healthy volunteers and patients with chronic visceral pain.

Since visceral pain is a multimodal sensory experience it is important to be able to activate the different pain modalities: mechanical, chemical and thermal. Recently the study team at Aalborg University, Denmark, have developed a probe with the capacity to activate these modalities selectively, and evaluating the specific responses to selective stimulations.

This information provides insight into which specific peripheral visceral receptors are sensitised. When stimulating the gastrointestinal tract experimentally in patients with chronic visceral pain, the study team have consistently found that they experience larger referred pain areas, indicating that the central nervous system is hyperexcitable. Such hyperexcitable stages can also be generated experimentally by perfusing the gut with acid. Such surrogate models of clinical pain conditions may help us understand more about visceral pain.

How were the study results collected?

To collect the study results, visceral stimuli were applied to healthy volunteers in the esophagus via a probe mounted on a balloon. The unique device was used to apply mechanical, heat pain and electrical pain stimuli. For stimulation in skin and muscles, electrodes (Figure 2), a pressure algometer and a 'thermo tester' were used. 24 subjects (12 women and 12 men) participated in this double blind, randomized experiment. After a baseline recording of the experimental pain, oxycodone (15 mg), morphine (30 mg) or placebo were randomly administered. Participant's pain responses were assessed in relation to the different pain stimuli, tested at baseline, 30, 60 and 90 minutes.

Summary of Study Results

-- Results from the study showed that both opioids had significantly better analgesic effect than placebo (all P values<0.001).

-- Most interestingly, the opioids were equally effective in all tissues except in the viscera, where oxycodone was shown to be more effective (P<0.001).

In the recent study, the team screened analgesics using a multimodal, multi-tissue pain assessment approach in healthy volunteers (the first time this methodology has been conducted). This means that in the same study, painful thermal, mechanical and electrical stimuli to the skin, muscle and viscera (oesophagus) were applied, providing an opportunity to assess the differentiated effect of new and existing drugs on specific tissues and specific pain modalities.

The team compared the effect of morphine and oxycodone in a placebo controlled study with the hypothesis that oxycodone, due to its possible kappa-agonist effects, may work better on visceral pain stimuli compared with morphine. They were able to differentiate between peripheral effects (a natural stimulus, e.g. thermal stimulation activates the peripheral receptors) and effects acting on the nerve conduction or on the central nervous system (electrical stimulation bypasses the peripheral receptors). As oxycodone was found to have the strongest analgesic effect on thermal visceral pain, the team concluded that oxycodone as compared with morphine acts more efficiently on the peripheral visceral nociceptors. It would be interesting to know if this effect is mediated by the kappa-opioid because we know from animal experiments that this receptor is up-regulated during visceral inflammatory conditions and hence it may provide a target for pain management.

Rationale for choosing study drugs

Treatment with traditional mu-opioid agonists, like morphine, often fail to relieve severe visceral pain. Furthermore, opioids with effect at the mu-receptor produce some well-known side-effects, such as sedation, nausea and constipation. New therapeutic approaches have involved the use of analgesics with effects at the kappa-opioid receptor. Analgesics effective at kappa-opioid receptors on peripheral nerves in the gut have also been considered, as they seem to mediate antinociception, whereas opioids with mu-effects may work at least partially in the periphery.

Unfortunately, however, the clinically useful kappa-agonists butorphanol and nalbuphine are of limited use because of their centrally mediated side effects and because they are partial agonists. More specific peripherally restricted kappa-agonists, like asimadoline, have shown effect in human visceral pain without centrally mediating side effects.

Animal studies using oxycodone have shown an effect at the kappa-opioid receptor and clinical experience is that this drug can work in opioid rotation in refractory visceral pain. The findings from animal visceral nociception studies combined with the limited knowledge about putative kappa-receptor agonist effects in humans, stresses the importance of further research in the clinical setting.

Clinical significance of the results

Results from clinical studies can be difficult to interpret, especially in visceral pain which is characterised by the diffuse and non-specific pattern of pain complaints. The results from this experimental study may, therefore, show with greater accuracy that a difference exists between different opioids with respect to attenuation of visceral pain. However, the results appear to indicate that oxycodone is more effective than morphine in the treatment of visceral pain in healthy volunteers, which may be consistent with clinical observations.

In the clinical setting oxycodone is often used in opioid rotation when the pain is resistant to morphine or other analgesics. As an experimental study can only give a trend, the clinician should consider whether the results fit into his or her patient population. It is questionable whether a valid clinical study comparing different opioids can ever be performed. The opinion of the study team is that such a study would be blurred by the many confounders related to diseases and patient heterogeneity. Therefore, the study would need to include a very large patient group and advanced statistical modelling to avoid overlooking important effects. It may be that clinicians would do better to use data directly from experimental studies to treat their patients. However, in this case the outcome should be assessed thoroughly as many pain mechanisms are brought into play in different patients and diseases, and the effect of analgesics will likely vary significantly.

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