Relentless fight against pain

Today, pain is properly assessed, recognised and managed in many medical situations: what may seem obvious is, however, the result of relatively recent changes in thinking and management methods, initiated in the 1990s. Alain Eschalier, Director of the Inserm/University of Auvergne Joint Research Unit at the Faculty of Medicine, Clermont-Ferrand, and a pharmacologist at the University Hospital, reviews this transformation.

Stop pain! The huge medical advances that have marked the last few decades have been accompanied by a growing collective awareness focused on improving pain relief. The refinement of analgesic drugs and of their use, the development of patient self-assessment of pain, increased acknowledgement of this pain by caregivers, the establishment of dedicated centres for pain management, government action plans, etc. are all advances from which patients are now gaining solace. At the same time, basic research conducted at Inserm and elsewhere has helped to improve understanding of the mechanisms involved in pain, and to identify the circuits for its transmission and modulation.

Changes in mentality

© Inserm, F. Guénet

"In the 1990s we witnessed a genuine change in mentality, with the transfer of pain assessment from the physician to the patient. There is no longer any question of a caregiver judging that such or such a treatment will be painful: s/he now asks the patient to describe his/her pain exactly, using assessment scales appropriate for the situation if necessary, and acknowledges it as such!” explains Prof. Alain Eschalier.* “At Ambroise Paré Hospital (Boulogne-Billancourt, 92), the team led by Didier Bouhassira** has, for example, developed a scale for neuropathic pains (Questionnaire DN4), which has been widely adopted internationally. In simple terms, it makes it possible to suspect the presence of these pains,” he says.

This increased recognition of pain has been accompanied by changes in practices, to improve management. During the same decade, recommendations and regulatory developments have, in particular, facilitated the use of analgesics, especially morphine and its derivatives: “Since that time, it has, for example been recommended that morphine-type drugs (opioids) be taken regularly, according to the duration of action of the selected drug, without waiting for the pain to return. It is also recommended that the opioid be replaced where there is poor tolerance, so as not to interrupt treatment. The advent of morphine pumps has also enabled administration controlled by the patients themselves, without abuse. At the same time, there have been developments in dosage forms: oral formulations of morphine type drugs, forms with prolonged release over several hours, or alternatively, immediate-release forms for rapid relief (especially for painful treatments), patches, etc. Everyone benefits from these advances, including the elderly and children,” explains Alain Eschalier. These practices have gradually become more widespread through their adoption by physicians, and with the help of funding released by the three action plans on pain voted by successive French governments between 1998 and 2010.

 

Mechanisms investigated

Although less visible, basic research has in its own way advanced knowledge throughout all these years. The development of animal research models and of medical imaging for humans (an area in which the team led by Luis Gracia Larrea*** has worked successfully) makes it possible to observe and describe the networks involved in the transmission of pain. “At Inserm, the unit led by Prof. Jean-Marie Besson was, for example, an international reference in the years 1980-1990, because of its work on the mechanisms of pain and pharmacology,” recalls Alain Eschalier. Among other things, this unit showed that morphine acts at the level of the spinal cord. This, for example, made it possible to develop epidural anaesthesia. The unit also described an endogenous negative feedback system of pain control (diffuse noxious inhibitory controls, DNIC), through work supervised by Daniel Le Bars. Basic and clinical research has also revealed the complexity of the pain process. It involves not only the activation of a sensory circuit, but also the activation of a diffuse network that interferes with cognition, emotions, behaviour, etc.

© Inserm, F. Scamps

Unfortunately, however, all these advances in the knowledge of pain have not enabled the development of major therapeutic innovations. “Of the new drugs that have appeared in recent decades, only the triptans, indicated for migraine, and ziconotide, obtained from conotoxins of animal origin, have resulted from basic research. Other novel developments, such as the use of antiepileptic drugs or antidepressants for neuropathic pain, come from clinical observations,” according to Alain Eschalier.

Room for therapeutic improvement

New treatments are needed, however: the current drugs have a benefit:risk ratio that could be considerably improved, regardless of the type of pain (from excess nociception in cases of trauma or cancer, neuropathic pain resulting from nerve damage, for example, or from organic dysfunction in the absence of an obvious lesion, such as seen in fibromyalgia). Indeed, although the morphine-type drugs are effective, they show many adverse effects (constipation, drowsiness, nausea, respiratory depression, risk of dependence, etc.). Paracetamol is well tolerated, but has a moderate effect. NSAIDs are effective but present gastrointestinal risks, risks of haemorrhage and renal failure, particularly in older people. Tricyclic antidepressants, a source of adverse effects, are only partly effective, and in only half of patients experiencing neuropathic pain. There is therefore genuine room for improvement!

© Inserm, M. Depardieu

On this point, Alain Eschalier’s team is attempting to describe the modes of action of analgesic drugs in current use, in order to discover new therapeutic possibilities and improve treatments. “For example, we are working on antidepressants for neuropathic pain, in order to understand why some of them are effective and not others. We are also trying to identify targets for paracetamol in the brain, in order to ultimately offer drugs that are more specific and more likely to be more effective. In collaboration with Michel Lazdunski and Jacques Noël from IPMC (Sophia Antipolis), we are also trying to dissociate the analgesic effect of morphine-type drugs from their side-effects, in order to design new, safer analgesics,” he says.

So many avenues, to which must be added anticipated new therapeutic targets, via continuing advances in basic research. In the 1980s, the team led by Bernard Roques worked hard on encephalins, endogenous opioids that moderate pain. Today, scientists are trying to strengthen their effect as an alternative to exogenous opioids (morphine-type drugs). New drugs may well emerge from this work.

The revolution in pain recognition has indeed happened, but the revolution in analgesics has therefore still to come.

 

Notes

*Inserm/University of Auvergne Unit 1107, Neuro-Dol, Clermont-Ferrand
**Inserm/Versailles-Saint-Quentin-en-Yvelines University Unit 987, Boulogne-Billancourt 
***Inserm/CNRS/University Claude-Bernard Lyon 1/ University Saint-Etienne-Jean Monnet Unit 1028, Neuropain, Lyon

Further information
For further information on pain, see our information pack (in french). 
Read also on the Histoire de l’Inserm (Inserm History) website: biographies of Jean-Marie Besson and Bernard Roques (in french).

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