Chronic Postsurgical Pain

By Gérard Mick

Primum non nocere… The fact that a surgical procedure can leave any kind of pain casts a shadow over this tenet, which is seen as the basis of medical practice and anchor of its principle ethic…

It is all the more surprising in that medicine has only paid attention to this paradoxical chronic pain situation for the past few years. Clarifying the knowledge acquired in this field has become all the more urgent for any care-giver today confronted by a legitimate request from patients: Why and how can a surgical procedure, which is supposed to bring relief, leave behind an unacceptable sequela?

This is the approach which the contributors to this new subject of major clinical interest invite you to follow as you work your way through this book.

• Language: English
• Publisher: Springer
• Release date: Feb 20, 2014
• ISBN: 9783319043227

Book preview

Part 1

Chronic Postsurgical Pain: General Aspects

Gérard Mick and Virginie Guastella (eds.)Chronic Postsurgical Pain201410.1007/978-3-319-04322-7_1

© Springer International Publishing Switzerland 2014

1. How to Study Chronic Postsurgical Pain: The Example of Neuropathic Pain

C. Dubray¹  

(1)

Clinical Pharmacology Center, Clermont-Ferrand Hospital, Auvergne University, Inserm CIC 501, 63003 Clermont-Ferrand Cedex, France

C. Dubray

Email: [e-mail]

Abstract

Chronic postsurgical pain (CPSP) is a common clinical situation which is still poorly assessed and often treated too late. An understanding of the neuropathic or inflammatory nature of CPSP will lead to an appropriate therapeutic approach. In everyday practice and in the majority of treatment studies, pain assessment is based on validated scales or questionnaires and simple clinical examination tools. Sophisticated investigations (electrophysiology, psychophysical techniques, or functional cerebral imaging) are reserved for pathophysiological studies or for clinical trials seeking to understand the mechanism of action of analgesic drugs. Postsurgical neuropathic pain (PSNP), due to its frequency, its relative homogeneity and its rather stereotyped time of onset, offers an excellent model for clinical research into neuropathic pain, which has been little used until now.

Key points

Chronic postsurgical pain (CPSP) is a common clinical situation which is still poorly assessed and often treated too late.

An understanding of the neuropathic or inflammatory nature of CPSP will lead to an appropriate therapeutic approach.

In everyday practice and in the majority of treatment studies, pain assessment is based on validated scales or questionnaires and simple clinical examination tools.

Sophisticated investigations (electrophysiology, psychophysical techniques, or functional cerebral imaging) are reserved for pathophysiological studies or for clinical trials seeking to understand the mechanism of action of analgesic drugs.

Postsurgical neuropathic pain (PSNP), due to its frequency, its relative homogeneity and its rather stereotyped time of onset, offers an excellent model for clinical research into neuropathic pain which has been little used until now.

Foreword

The assessment of CPSP is approached very differently in a context of ongoing treatment, a treatment study or a study looking at the pathophysiological processes involved.

In everyday practice it is essential to identify the neuropathic or non-neuropathic character of the pain reported by the patient, since this determines the approach to treatment. These diagnostic aspects, which are also considered in other chapters in this book, are essentially based on clinical examination and on questioning guided by the specific tools (questionnaires and scales) developed and validated over the last 10 years [1–3].

Neuropathic pain is usually associated with positive symptoms in the form of pain and negative symptoms in the form of a neurological deficit. The positive symptoms may consist of pain of various types: spontaneous pains, either continuous pain like a superficial burning sensation, a deep vice-like pain or painful cold; the sensations may be paroxysmal like an electric shock or very brief like stabbing; the pain may be caused by mechanical stimulation (friction, pressure) or thermal stimulation, resulting either in allodynia (pain caused by stimuli that are not usually painful) or hyperalgesia (reduction of pain perception thresholds). The painful areas are also where deficit signs are also noted, in the form of hypoaesthesia or anaesthesia in one or two sensory modalities (temperature sensation, vibration sense, joint position sense, fine touch or pain sensation) [6].

These clinical features are elicited using simple examination tools. The following can be used: (1) a ball of cotton wool, the corner of a swab, a cotton bud or an artist’s brush to look for hypoesthesia to touch or allodynia to (dynamic mechanical) friction; (2) a neurological tuning fork to study vibration sense and cold sensation (the metallic handle placed on the table is at a temperature of 20 °C on average and is normally perceived as cold); (3) a calibrated monofilament (Semmes-Weinstein type for diabetology or Von Frey type in neurology) to look for hypoaesthesia, hyperalgesia or allodynia to point pressure; (4) finally a blunted point (needle) for pain perception [6, 19, 22, 23]. These tests are carried out in the areas that are painful, guided by the symptoms described by the patient and most commonly (but not exclusively) in the extremities and distal to the patient’s scar from surgical access. It is possible through a detailed examination to produce a real map of areas that are painful, allodynic, hyperalgesic and hypoaesthetic, and these areas are not always perfectly overlapping (Fig. 1.1).

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Fig. 1.1

Example of the topographical distribution of sensory abnormalities after thoracotomy. The red line represents the scar; the area shaded in blue is an area of hypoaesthesia; the yellow and black checkered area is a zone of hyperalgesia (static mechanical stimulation) and allodynia (dynamic mechanical stimulation)

In the context of treatment or pathophysiological research, on which we will focus our attention, the problems of assessment that arise take different forms depending on whether the painful symptoms are the result of inflammatory phenomena associated with the fibrotic process, or whether they are neuropathic and therefore secondary to the section, compression/ischaemia, avulsion or crush injuries to nerve trunks and nerve endings. Here we will only address the assessments used for chronic pain with a neuropathic character which occurs following a surgical procedure, since: (i) this is a common clinical situation according to epidemiological surveys, since 5–40 % of patients undergoing surgery will, depending on the type of operation, present with neuropathic pain as a result. This public health problem therefore deserves specific attention [9, 10, 15, 16]; (ii) that they offer opportunities for precise chronological monitoring starting from the day of the operation, with the possibility of a baseline reference during the immediate preoperative period. These conditions are, a priori, much more amenable to clinical studies than the majority of other causes of neuropathic pain. They certainly provide a useful model for both the assessment of new treatments and the study of pathophysiological mechanisms.

Treatment Studies in Patients Presenting with PSNP

PSNP is one of the rare etiologies that make it possible easily to design both preventative and curative studies.

Clinical Studies of Preventative Treatments

The patients included in studies of this type will preferably be those who need to have an operation which is known a priori to be an important inducer of neuropathic pain (mastectomy, sternotomy, thoracotomy). It should be remembered that thoracotomies, for example, create a virtually experimental injury to a subcostal nerve, which is compressed for a long period (crushing/ischaemia) by the retractors used to open the thoracic cage [14, 15]. In a treatment study**/trial of this type, care must be taken not to include patients who present with pre-existing neuropathy and to avoid those who, a priori have to be exposed to other factors that facilitate the occurrence of neuropathic pain in an identical or nearby territory, such as chemotherapy or radiotherapy.

The organisational structure for a randomised, controlled, double-blind trial of this kind is quite stereotypical. The patients are pre-selected during the preoperative period and when they have been enrolled they are allocated by prior randomisation to a particular type of preventative treatment: the study product versus the reference product, which will be administered during the immediate peri- or postoperative period. The preventative efficacy of these treatments is assessed by comparing the incidence and severity of the neuropathic pain that occurs long after the procedure, with a period of follow-up extending to at least 6 months.

Clinical Treatment Studies with a Curative Aim

Two situations can be imagined, and these do not yield the same information.

Enrolment of patients presenting with chronic pain with a neuropathic character that has occurred subsequent to a surgical intervention, seen in outpatients (for example in a pain assessment and treatment unit), once the pain has been evolving over several months or several years. These patients do not differ much in a number of respects from those who are traditionally included in the treatment trials (with diabetic neuropathy or post-zoster pain). They generally have a complex clinical history, which is punctuated with multiple treatment failures and it is often difficult for ethical reasons to stop some of their analgesic medications because these do have some efficacy, even if this is only modest. Under these conditions, these treatment studies are in fact add-on drug studies rather than specific assessments of a given molecule.

The same situation also arises in the usual clinical studies that were referred to previously, and the principal advantage of carrying out the study in patients suffering from postsurgical neuropathic pain is the high incidence of this situation and the resulting high potential for enrolment of patients.

Enrolment of patients during the preoperative period with a view to prospective follow-up intended to identify the occurrence of chronic pain at an early stage.

This approach requires regular follow-up of patients from the first few weeks following the intervention (telephone calls or outpatient appointments), with the aim of detecting the occurrence of neuropathic pain as soon as its first clinical signs or symptoms appear. Having confirmed the neuropathic nature of any pain that occurs during the postoperative period, the patient will be allocated by randomisation to either receive a medication or the control. The evolution of the pain symptoms in each of these two groups will form the basis for comparing the efficacy of the treatment. The advantage of this approach is that it makes it possible to evaluate the effect of a molecule which is not combined with other treatments, except, of course, the use of an emergency analgesic which should be identical in both groups.

In all treatment trials, the understanding of the efficacy of treatments for pain symptoms is based on the use of validated scales to assess the intensity of the overall pain and also of spontaneous and provoked components and measure the impact on quality of life [1]. If one wishes to go further towards an understanding of the mechanism of action of some of the medications studied in the context of these treatment trials, it will be necessary to include the sophisticated investigations presented in the next chapter.

Pathophysiological Studies of PSNP

As in the case of treatment studies, PSNP is a model which is particularly well suited to pathophysiological research into the mechanisms leading to the occurrence and evolution of chronic post surgical pain symptoms. As far as possible, prospective studies will be used that make it possible to monitor chronologically the occurrence of the pain during the postoperative period. It makes sense in this context to use specific functional investigations that are intended to identify and quantify the peripheral nerve injuries and pain pathway sensitisation processes that create the foundation for neuropathic pain. These approaches exist alongside the tools for the clinical assessment of neuropathic pain that have been described above in relation to treatment trials.

Electrophysiological and Psychophysical Techniques

In clinical electrophysiology, the main techniques used are electroneuromyography (ENMG) and traditional somatosensory evoked potentials (SEPs), triggered by electrical stimulation of territories that are painful and show deficits. These methods, possibly supplemented by the use of a vibrameter (Vibrameter™ Somedic) or a graduated tuning fork only make it possible to study the lemniscal system and consequently the A-beta myelinated fibres. These investigations are therefore inadequate, since large-calibre myelinated fibres are generally considered not to play a major role in the genesis of neuropathic pain [17, 24].

Study of the Functionality of A-Delta and C Fibres

Quantitative sensory analysis ( Quantitative Sensory Testing or QST ) is based on psychophysical approaches. This involves applying stimuli (mainly mechanical or thermal in nature) at an amplitude modulated by the experimenter and studying the sensory perceptions (whether painful or otherwise) felt by the patient. It should be noted that mechanical stimulation (compression or pinprick) or cold temperature stimulation essentially explore A-delta fibres, while hot temperature stimulation explores C fibres. This method of analysis is based on QST and makes it possible to identify and above all quantify hyperalgesia or allodynia. For every patient, the thresholds for these two types of provoked pain may then be confirmed with reference values (for a reference population). It is preferable, however, to carry out symmetrical studies of the healthy side and the injured side (on which the operation was carried out), working at the level of the zones in which the neuropathic pain occurs in combination with hypoaesthesia.

Mechanical sensitivity can be determined either statically or dynamically. In the case of static stimulation, either calibrated Von Frey monofilaments will be used or the electronic Von Frey system Bioseb™ with point pressure, or else a pressure algometer (Somedic Algometer™) with wide static stimulation. These two appliances quantify the pressure applied and supply a numerical value (in g or in kPa) for the pain sensation threshold.

Dynamic mechanical stimulation is applied by moving a brush or paintbrush across the surface of the skin. The pain evoked is quantified using a visual analog scale (VAS) or a simple numerical scale (SNS).

Temperature and pain sensation are quantified precisely using a thermode which works on the principle of the Peltier effect, making it possible to vary the temperature of the thermode between 5 and 52 °C with a precision of approximately 0.1 °C (Somedic Thermotest™; TSA-II™ or Medoc Pathway™).

Combining these various quantitative sensory analysis techniques makes it possible to create an individual profile which can evolve over time and expresses the plasticity of the pathophysiological processes that are involved [31]. Completing the full range of QST tests takes quite a long time and demands a minimum level of experience on the part of the experimenter in order to be reproduced reliably [32, 33]. It however makes sense to think that this individual profile could prove very useful for the purpose of classifying patients and allocating them to the various arms of a prospective or interventional treatment trial. This process is one of the most promising research approaches in order to optimise the targeting of a given molecule for specific indications. Integrating it into the process of clinical development of new medications that may have potential actions for the alleviation of neuropathic pain undoubtedly makes the clinical trials more burdensome to implement (time required for investigations, number of arms in the trial, other factors) but the expected benefits in terms of optimising therapeutic management appear to be considerable.

The pain potentials evoked by laser stimulation (PESTL) make it possible to stimulate painful temperature receptors (A-delta and C fibres) without cutaneous contact and therefore without concomitant stimulation of rapid afferent fibres (A-beta).

The laser is a radiant thermal source in the infra-red band, used for brief periods of stimulation (10–50 ms), which easily penetrates the epidermis and produces a double painful sensation: a first rapid pin-prick type pain transmitted by A-delta fibres, then a second sensation of pain that appears a little later, diffuse and burning in nature and persisting for a while after application of the stimulus. Recording of evoked potentials is always based on the same principle, which involves placing the cutaneous electrodes facing towards the cranial cavity in order to record an electroencephalographic trace and using them to synchronise the sequences of signals with the laser stimulation. Supraliminal thermal stimulation (i.e. slightly above the pain threshold determined beforehand for each patient) are therefore repeated 15–30 times in order to identify the pain stimulus response signal against the background noise of cerebral activity.

In patients presenting with peripheral neuropathic pain, the primary interest is in a cortical response, either late and dependent on A-delta fibres, or ultra-late and dependent on C fibres. Injuries of peripheral nerve fibres are translated into abnormalities of cortical potentials: these are absent, delayed or their amplitude is reduced in comparison with the homologous healthy contralateral territory or reference values [4, 7, 8, 27]. The use of this technique is being developed in multiple centres where chronic pain is being researched; this may make it possible to combine it with the quantitative sensory analysis methods described previously. Other electrophysiological techniques have more limited applications;

the nociceptive flexion reflex (RIII) or the trigeminal reflexes only occur in specific territories and are useful mainly for exploring the responsiveness of descending inhibitory tracts in pathological contexts [30];

microneurography is much more limited in the scope of its use because it is more invasive and technically difficult. It involves placing electrodes in direct contact with peripheral nerve fibres and recording their potential in order to evaluate their function [24].

Functional Cerebral Neuroimaging

These non-invasive techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are becoming increasingly important in the investigation of both acute and chronic pain [21, 26]. As in the case of evoked potentials, the conditions under which these investigations are carried out and interpreted require specific competencies which are only available in a small number of specialist centres. So far very few studies of PSNP have made use of these techniques, which is unfortunate because the features of this clinical model, particularly the precise chronological follow-up, ought to make its use attractive in pathophysiological and treatment research into neuropathic pain (Table 1.1).

Conclusion

Due to the frequency of its occurrence in the population and its characteristics, PSNP is a clinical model which is particularly well suited for use in treatment studies of new molecules and pathophysiological studies. The choice of investigation is directly dependent on the aims of the individual study, the equipment available and the experience of the investigators. It must, however, be remembered that a methodological clinical examination, using validated scales and simple tools, still offers opportunities to conduct excellent treatment studies.

Table 1.1

Assessment methods used to examine nerve function

ENMG electroneuromyography, SEP somatosensory evoked potentials, NEP nociceptive evoked potentials

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