Applying Contemporary Pain Neuroscience for a Patient With Maladaptive Central Sensitization Pain

Jo Nijs, Margot De Kooning, Anneleen Malfliet, Mark A. Jones

A Brief Background of Pain Neuroscience

Despite extensive global research efforts, chronic ‘unexplained’ pain remains a challenging issue for clinicians and an emerging socioeconomic problem. Pain neuroscience has evolved, and musculoskeletal clinicians around the globe are at the front line for implementing contemporary pain neuroscience in clinical practice.

Contemporary pain neuroscience has advanced our understanding of pain. The initial paradigm was pain proportional to nociceptive input; the second was Wall and Melzak’s gate theory (Wall and Melzack, 1994), and the most recent is pain as central sensitization (CS). Peripheral sensitization and, to some extent, also CS, occurs normally with acute pain but normally decreases soon after the inflammatory phase. Therefore, here we conceptualize the sensitization in chronic pain as ‘maladaptive central sensitization’ (referred to as nociplastic pain elsewhere in this book). For brevity reasons, maladaptive central sensitization in chronic pain is abbreviated throughout this chapter as CS pain. It is now well established that sensitization of the central nervous system (CNS) is an important feature in many patients with chronic pain, including those with whiplash (Van Oosterwijck et al., 2013b), shoulder impingement syndrome (Paul et al., 2012), chronic low back pain (Roussel et al., 2013), osteoarthritis (Lluch Girbes et al., 2013), headache (Ashina et al., 2005; Perrotta et al., 2010), fibromyalgia (Price et al., 2002), chronic fatigue syndrome (Nijs et al., 2012c), rheumatoid arthritis (Meeus et al., 2012), patellar tendinopathy (van Wilgen et al., 2011), and lateral epicondylalgia (Coombes et al., 2012; Fernandez-Carnero et al., 2009). Also, neuropathic pain may be characterized/accompanied by sensitization; peripheral and central (segmentally related) pain pathways can become hyperexcitable in patients with neuropathic pain.

CS has been defined as ‘an amplification of neural signaling within the central nervous system that elicits pain hypersensitivity’ (Woolf, 2011) or ‘an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors’ (Meyer et al., 1995). Such definitions originate from laboratory research, but the awareness that the concept of CS should be translated to the clinic is growing, which is illustrated by the present case report.

CS encompasses various related dysfunctions of the CNS, all contributing to an increased responsiveness to a variety of stimuli, such as mechanical pressure, chemical substances, light, sound, cold, heat, stress and electrical stimuli (Nijs et al., 2010). Such dysfunctions of the CNS include altered sensory processing in the brain (Staud et al., 2008), malfunctioning of descending anti-nociceptive mechanisms (Yarnitsky, 2010; Meeus et al., 2008), increased activity of pain facilitatory pathways and enhanced temporal summation of second pain or wind-up (Filatova et al., 2008; Raphael et al., 2009). In addition, the pain (neuro)matrix is overactive in CS and chronic pain, with increased brain activity in areas known to be involved in acute pain sensations (the insula, anterior cingulate cortex and the prefrontal cortex) as well as in regions not involved in acute pain sensations (various brainstem nuclei, dorsolateral frontal cortex and the parietal associated cortex) (Seifert and Maihofner, 2009).

Musculoskeletal practice has come a long way in terms of integrating the understanding of contemporary pain neuroscience. Pain neurophysiology has traditionally been one of the cornerstones of musculoskeletal practice, making it easier for us to understand new concepts like CS. Still, clinicians struggle with the treatment of CS pain. Given the complexity of the mechanisms behind CS pain and the lack of evidence-based treatment for CS pain, this comes as no surprise. Here we illustrate how musculoskeletal clinicians can apply contemporary pain neuroscience in a patient with chronic (neck) pain. The majority of the reasoning outlined herein applies to many chronic pain patients rather than being specific for (traumatic) neck pain only.

History

Anna is a 37-year-old female patient who suffered a traumatic neck injury due to a car accident 8 years before she entered our practice upon referral from a physician specialized in rehabilitation medicine. She was driving the car herself and was wearing a seatbelt. The day following her car accident, she went to work (full-time teaching at a university college) but experienced difficulties concentrating and suffered from a headache and increased sensitivity to bright light as well as sound. After work, she consulted her family physician, who referred her for x-rays of her cervical spine and prescribed sick leave. After 3 months of sick leave, she was obliged to return to work according to the local insurance system. Because she felt unable to resume work, she took her available holidays. In total, she didn’t return to work until 2 years post-injury.

The initial imaging findings (x-rays and nuclear magnetic resonance [NMR] imaging of the cervical spine and the brain) were rather limited, showing nothing but slight degeneration of the C4–C5 facet joints and anterior bulging of the C5–C6 disc. The NMR re-assessment 3 years later showed similar findings without progression. A third NMR scan a few months before she entered our practice confirmed the lack of progression.

Since her car accident up to her first attendance in our practice, Anna had developed severe chronic whiplash-associated disorder (WAD), including shoulder and neck pain radiating to her arms, headache, concentration difficulties, fatigue, sleeping problems and hypersensitivity to bright light and sound. Anna described her shoulder, neck and arm pains as ‘fatiguing and vague’. She sometimes experienced sensory loss in both arms (including the hands), but these symptoms would come and go. Anna did not report any other new-onset hypersensitivity symptoms such as increased sensitivity to smell and hot or cold sensations. She also had extensive previous screening for neurological and arterial symptoms, which were negative. Anna experienced difficulties (variable provocation of neck, shoulder, arm pains and headache) undressing, lifting, walking or standing for a long time, looking down and upward, and during household activities (especially repetitive overhead activities). She used to be good at coping with stress, but in the last couple of years, she had been very irritable, anxious and ineffective at coping with everyday stressors. At the time of the initial appointment, Anna was able to work full-time, but besides working, she had little energy left for other activities. Notably, her social activities, including catching up with friends, were at a very low level, much lower than she would like.

Anna is happily married with two lovely children of 3 and 6 years. Her husband is very supportive of her medical problems. Her symptoms have been fluctuating over time ever since her car accident.

Anna has no other health conditions (comorbidities) and has never been diagnosed with any other long-term illness. She has no history of unexplained weight loss or any other red flag.

In the early phase post-injury, she was advised by her treating physician to wear a collar and to continue wearing it whenever necessary. She tried physiotherapy several times, with mixed results and only small, non-lasting improvements in pain. Treatments included exercise therapy, massage, electrotherapy and heat therapy. At the moment, she is taking muscle relaxants and painkillers (acetaminophen) depending on pain severity, which offer some relief, but she indicates that they appear to work less effectively than they used to.

Questionnaires

The Pain Catastrophizing Scale (Sullivan et al., 1995) generated a total score of 30/52, with a normal score on the subscale of pain magnification (5/12) but high scores on the helplessness (15/24) and rumination (10/16) subscales. The brief Illness Perceptions Questionnaire (Broadbent et al., 2006) revealed that Anna thought that increased muscle tension and doing too much caused her sustained disability, did not understand her health problem, believed that her pain would last for a long time, worried a lot about her health problem and was unable to find a cure or way to self-control her pain. Finally, the Pain Vigilance and Awareness Questionnaire (Roelofs et al., 2003) clearly revealed pain hypervigilance.

Reasoning Question:

1. Would you comment on your choice of questionnaires and your use of the information obtained? Also, were there issues regarding Anna’s ‘perspectives on her experience’ that emerged in her questionnaire responses and/or her interview/history that you noted for returning to at later appointments to explore further with Anna?

Answer to Reasoning Question:

There are so many questionnaires we can use. Although they generate very useful information for clinicians, patients generally don’t like filling them out, and considerable time is required for interpreting them. Hence, it is important to be selective in the choice of questionnaires. A classic mistake clinicians make is using questionnaires to decide which type of pain they are faced with. Unless you are willing to use a diagnostic neuropathic pain questionnaire, this is not advised. In fact, maladaptive pain cognitions can be present in any patient, regardless of whether patients have nociceptive, neuropathic or CS pain. It is important to realize that we do not use these questionnaires for diagnostic purposes but, rather, for identifying treatment goals and informing our client-centred pain neuroscience education. Indeed, pain neuroscience education should always try to address the maladaptive pain cognitions and illness perceptions (van Wilgen et al., 2014). While the Pain Catastrophizing Scale and Pain Vigilance and Awareness Questionnaire often generate clear findings from scoring the answers and computing the results, the brief Illness Perceptions Questionnaire often identifies patient perceptions that require further, more thorough exploration. This is, in fact, an enjoyable part of the history taking, as you often hear amazing stories from patients who have adopted strange illness perceptions from family members, friends, neighbours or even other healthcare providers!

Regarding ongoing assessment of Anna’s perspectives through later appointments, we continuously assessed them through questioning Anna’s perceptions about changes in pain severity throughout the treatment period (i.e. the fluctuating nature of her pain), as well as her perceptions about (anticipated) pain increases following exercises and daily activities.

Clinical Reasoning Commentary:

Here an important distinction is highlighted regarding obtaining patient information to diagnose or categorize versus obtaining patient information to inform understanding and management and to monitor change. In the ‘hypothesis categories’ framework presented in Chapter 1, we encouraged a balance in reasoning between ‘pathology’ and ‘impairment’. A similar balance is needed between categorizing the type of pain and understanding the patient’s perspectives. They both have direct implications for management and prognosis, and hence both are important. But as emphasized in this answer, questionnaires on their own mostly will not provide a diagnosis of pain type. Their primary value is what they reveal regarding patient perspectives. This is highlighted in the point made about exploring patients’ responses to the brief Illness Perceptions Questionnaire further. Three patients may tick the same questionnaire box, provide the same score to a stated perspective or provide the same written illness perception, but for quite different reasons. Although the questionnaire can be re-administered to assess change, for this information to be most useful in informing management, the clinician needs to clarify apparent maladaptive/unhelpful responses to better understand the basis of those responses.

Assessment to inform clinical reasoning is never completed in a single appointment. This is particularly the case for the continued assessment of patient perspectives (i.e. psychosocial status) that the authors highlight throughout the ongoing management.

Clinical Examination

On examining her posture in standing and sitting, no major issues were identified. Anna’s passive physiological and accessory cervical joint mobility was normal (full range of motion at all levels and in all directions with no provocation of symptoms), but active cervical mobility in sitting was restricted toward flexion, and combined neck extension and rotation to the left and the right was painful and restricted. She indicated she was afraid to hurt her neck when performing the active movements. The examination of her shoulder complex was negative. Her breathing pattern was normal, including the coordinated action of the thoracic cage with the abdomen. Anna tested positive on the craniocervical flexion test, showing impaired deep cervical neuromuscular control, with clear overshooting of the requested movements (Jull et al., 2008). Anna had moderately increased cervical muscle tone limited to the cervical muscles (trapezius, scaleni and upper cervical muscles) but no active trigger points. As is often the case in patients with chronic WAD, the outcome of the examination of neurodynamic tests (previously known as brachial plexus tests or upper limb tension tests) was rather vague and did not generate a consistent picture of restricted mobility or symptom provocation consistent with any of the major upper limb nerves (median, ulnar, radial).

In addition, we used a hand-held analogue Fisher algometer (Force Dial model FDK 40 Push Pull Force Gage, Wagner Instruments, P.O.B. 1217, Greenwich CT 06836) for assessing pressure pain thresholds at three anatomical locations: the right trapezius belly (midway between the spinous process of T1 and lateral part of the acromion), her right hand (midpoint of the first metacarpal) and the midpoint of her right calf. In order to determine pressure pain thresholds at each location, pressure was gradually increased at a rate of 1 kg/s until she reported the first onset of pain (at which point Anna said ‘stop’).

Next, for assessing the functioning of brain-orchestrated endogenous analgesia, conditioned pain modulation was induced by inflating an occlusion cuff (conditioning stimulus) around Anna’s left arm (midway of her upper arm) to a painful intensity (Daenen et al., 2013b). The occlusion cuff was inflated at a rate of 20 mmHg/s until ‘the first sensation of pain’ was reported. This cuff inflation was maintained for 30 seconds. Afterward, Anna was asked to rate the pain intensity, as a result of cuff inflation around the left arm, on a numerical rating scale (0 = no pain to 10 = worst possible pain). Next, the cuff inflation was increased or decreased until pain intensity at the left arm was rated as 3/10 on the verbal rating scale. Then the previously described pressure pain thresholds were repeated during maintenance of the cuff inflation and relaxation of the left arm. This way of assessing conditioned pain modulation has revealed impaired endogenous analgesia in patients with chronic WAD (Daenen et al., 2013b) and allows performance in a clinical setting. Anna’s results at the baseline pain threshold measurements and the change during conditioned pain modulation indicated dysfunctional endogenous analgesia in the lower limb (from 6.8 kg/s at baseline to 7.2 during cuff inflation) and the neck (from 2.0 kg/s to 2.6), but not at the hand (7.2 kg/s to 13.4).

Contrary to her ability to activate pain inhibition at rest, Anna was able to activate endogenous analgesia in response to a short, low-intensity, graded bicycle test (4 minutes of stationary cycling starting from 50 watts increasing by 25 watts per minute). This was shown by the increases in manually assessed pressure pain threshold at the right hand (increase from 8.25 kg/s at baseline to 9.20 immediately post-exercise) and right lower limb (6.8 kg/s to 10.6). The small increase in pressure pain threshold at the right hand should not be interpreted as an important change, but the fact that it did not decrease as is often seen in chronic pain patients (Nijs et al., 2012), together with the observed increased pain threshold at her right lower limb, supports a physiological activation of endogenous analgesia during exercise.

Fig. 25.1 Algorithm for the differential diagnosis of nociceptive versus central sensitization pain. (Modified from Nijs et al. [2014].)

Reasoning Question:

2. In your opening background on pain neuroscience, you explained what maladaptive CS is and discussed its contribution to chronic ‘unexplained’ pain. Would you discuss how you differentiate neuropathic, nociceptive and CS pain and highlight the key features from Anna’s history and clinical examination that support or refute a dominant CS pain mechanism? Also, would you presume that Anna initially had some level of soft tissue injuries, and if so, can you identify any likely factors in her history that may account for her progression to CS and chronic pain?

Answer to Reasoning Question:

Any pain complaint can be either nociceptive, neuropathic or CS in nature, and combinations are also possible (e.g. neuropathic and CS pain). We used the information from Anna’s history, and later her clinical examination, for differentiating nociceptive, neuropathic and CS pain. For that, diagnosing or excluding neuropathic pain is often the first step in musculoskeletal practice. Indeed, although recent guidelines have been published for classification of neuropathic pain (Treede et al., 2008; Haanpää M, 2010), the criteria specify that a lesion or disease of the nervous system is identifiable and that pain is limited to a ‘neuroanatomically plausible’ distribution. These criteria, however, preclude the use of the term ‘neuropathic pain’ for people with widespread pain and nervous system sensitization (i.e. CS pain).

We used the five questions that follow to examine the odds of a neuropathic cause for Anna’s pain (Treede et al., 2008; Haanpää, 2010). It is important to note the issue of sensory dysfunction for the differential diagnosis between neuropathic and CS pain. Sensory testing is of prime importance for the diagnosis of neuropathic pain (Treede et al., 2008; Haanpää, 2010). This includes testing of the function of sensory fibers with simple tools (e.g. a tuning fork for vibration, a soft brush for touch, and cold/warm objects for temperature), which typically assesses the relationship between the stimulus and the perceived sensation (Haanpää, 2010). Several options arise here, all suggestive of neuropathic pain: hyperesthesia¹, hypoesthesia², hyperalgesia³, hypoalgesia⁴, allodynia⁵, aftersensations and so forth. Whereas in neuropathic pain the location of the sensory dysfunction should be neuroanatomically logical, in CS pain it should be spread in non-segmentally related areas of the body. Clinical examination in CS pain typically reveals increased sensitivity at sites segmentally unrelated to the primary source of nociception (Sterling et al., 2004; Nijs et al., 2010).

1. Is there a history of a lesion or disease of the nervous system, either central or peripheral nervous system? No, there was not in this case. Unless the traumatic event resulted in damage to the nervous system, which would preclude diagnosing WADs grade I to III (Spitzer et al., 1995), this is rarely the case in such patients. There was no evidence from Anna’s diagnostic investigations to reveal an abnormality of the nervous system or post-traumatic damage to the nervous system (not in the spinal cord, peripheral nerves or brain).
2. Does the patient present with comorbidities often related to neuropathic pain (e.g. cancer, stroke, diabetes, herpes or neurodegenerative disease)? No, Anna does not present with such comorbidities.
3. Is the pain distribution neuroanatomically logical? No, the pain distribution is neuroanatomically illogical. Anna presents with neck pain combined with headache and pain in both shoulders, sometimes radiating to both arms/hands.
4. Does the patient describe the pain as burning, shooting, or pricking? No, instead Anna described the pain as fatiguing and vague.
5. Is the location of the sensory dysfunction neuroanatomically logical? Again no: Anna sometimes experiences sensory loss in both arms (including the hands), but these symptoms come and go.

From the reasoning evident in the answers to these questions, it becomes clear that Anna does not have neuropathic pain. In cases of neuropathic pain, these questions should be answered positively. This leaves us with three options: nociceptive, CS pain or both.

For differentiating nociceptive and CS pain, clinicians can use the algorithm presented in Fig. 25.1. The algorithm guides the clinician through the screening of three major differential criteria, each of which is explained in the following subsections with reference to Anna’s case. The criteria are taken from a recently published international proposal for the classification of CS pain, which is based on a body of evidence from original research papers and expert opinion from 18 pain experts from seven different countries (Nijs, 2014). Although an increasing number of musculoskeletal clinicians have been trained in using these criteria in clinical practice, studies examining the validity of these criteria are currently unavailable (however, they are ongoing).

Criterion 1: Pain Experience Disproportionate to the Nature and Extent of Injury or Pathology (Nijs, 2014)

This first criterion is obligatory and implies that the severity of pain and related reported or perceived disability (e.g. restriction and intolerance to daily life activities, to stress, etc.) are disproportionate to the nature and extent of injury or pathology (i.e. tissue damage or structural impairments). This is in contradiction to nociceptive pain, where the severity of pain and perceived disability are proportionate to the nature and extent of injury or pathology and physical impairments.

For screening of this first criterion, we initially considered the degree of Anna’s injury and pathology against her reported pain and disability. Several imaging techniques were used to identify such nociceptive sources, but neither initial imaging (x-ray and NMR of the cervical region and the brain) or follow-up imaging 9 years post-injury (NMR of the cervical region and the brain) were positive. The increased muscle tension was limited in severity and restricted to the cervical muscles (trapezius, scaleni and upper cervical muscles). In addition, the clinical examination revealed dysfunctional neuromuscular control of the deep cervical flexors, as often seen in patients with chronic WAD (Elliott et al., 2010; Sterling et al., 2003b).

Next, we weighted the degree of injury, pathology and physical signs against her reported pain, disability and tolerance to activities of daily living for the likelihood of a dominant nociceptive input being responsible for her pain experience. We asked ourselves: Are Anna’s evidence of injury, pathology and physical signs sufficient to account for her pattern of symptom behaviour as expected for a dominant nociceptive source? It was concluded that the functional difficulties Anna’s was having were associated with too variable a pattern of symptom provocation to support a hypothesis of nociceptive pain. It was concluded that the limited muscle tension was neither able to explain the complexity of her symptoms and other signs nor capable of explaining her pain experience. After all, she had tried hands-on myofascial treatment before, with very limited benefits. In addition, research has taught us that the dysfunctional neuromuscular control of the deep cervical flexors in patients with chronic WAD is of limited clinical importance (Daenen et al., 2013a). Therefore, and in addition to our conclusion regarding the increased cervical muscle tone, it was decided that the dysfunctional neuromuscular control of the deep cervical flexors was also unable to explain the pain experienced by Anna. Hence, it was reasoned that she suffered from disproportionate pain.

Criterion 2: Diffuse Pain Distribution (Nijs, 2014)

For screening this criterion, a thorough assessment and interpretation of the patient’s self-reported pain distribution are required. Examples of patterns of pain distribution that fulfill this criterion are bilateral pain/mirror pain (i.e. a symmetrical pain pattern), pain varying in (anatomical) location, large pain areas with a non-segmental (i.e. neuroanatomically illogical) distribution, widespread pain and/or allodynia/hyperalgesia outside the segmental area of (presumed) primary nociception (Nijs, 2014).

As explained previously, Anna had a pattern of pain distribution that complies with this criterion; she showed evidence of diffuse pain distribution (i.e. pain varying in location and large pain areas with a non-segmental distribution). Thus, the first two criteria are met, which is sufficient for classifying her pain as CS pain (Fig. 25.1). For comprehensiveness, the screening of criterion 3 is explained as well.

Criterion 3: Hypersensitivity of Senses Unrelated to the Musculoskeletal System (Nijs, 2014)

CS may manifest as much more than generalized hypersensitivity to pain: it may be characterized by an increased responsiveness to a variety of stimuli in addition to mechanical pressure, namely, chemical substances, cold, heat, electrical stimuli, stress and emotions. It is therefore recommended to question patients with suspected CS for new-onset hypersensitivity to bright light, sound, smell and hot or cold sensations. In this case, Anna reported suffering from hypersensitivity to light and sound. The screening for criterion 3 can be done using part A of the Central Sensitization Inventory (Mayer et al., 2012), which assesses symptoms common to CS, with total scores ranging from 0 to 100 and a recommended cutoff score of 40 (Neblett et al., 2013). At the time we assessed Anna, the Central Sensitization Inventory was not yet available.

Taken together, Anna fulfilled all three criteria for classifying her pain as CS pain. This does not imply that there is no (relevant) nociception contribution (for instance, in her cervical muscles); it only implies that central mechanisms rather than peripheral factors are dominating her clinical picture. The fact that Anna’s signs and symptoms are dominated by CS comes as no surprise. There is consistent evidence for CS pain in patients with traumatic neck pain (i.e. chronic WAD), as shown by two independent systematic literature reviews (Van Oosterwijck et al., 2013b; Stone et al., 2013). Both reviews concluded that CS should be considered in the management of chronic WAD. The fact that during clinical examination her brain-orchestrated endogenous analgesia (conditioned pain modulation) at rest was deemed dysfunctional further supports the presence of CS pain.

Clinical Reasoning Commentary:

Diagnostic ‘differentiation’ classically refers to consideration of ‘pathologies’ or possible ‘sources of symptoms (e.g. nociception) responsible for a patient’s pain and physical signs. Here the authors apply the concept of differential diagnosis to the type of pain. ‘Pain type’ is an essential ‘hypothesis category’ (see Chapters 1 and 2) that must be reasoned alongside traditional structure/tissue/pathology differentiation when, for example, a hypothesis of a dominant CS pain moderates the clinician’s interpretations of traditional physical tests for sources of nociception that may be false positives, that is, provocative due to CS and not local tissue ‘injury’. Although the reasoning reflected in this answer supports that patient information was interpreted as it emerged, first-appointment hypotheses are not concluded until the examination is completed. Judgements are deduced on the basis of best available evidence, drawing from the congruity and proportionality of findings within and between the history/subjective examination (e.g. area of symptoms, behaviour of symptoms, nature and extent of injury or pathology, relevant comorbidities) and the clinical/physical examination (e.g. physical impairments, sensory testing). That is, when possible, reasoning judgements should be transparently linked to the synthesis of specific assessment findings.

¹Hyperesthesia is increased sensitivity to sensory stimuli.

²Hypoesthesia is decreased sensitivity to sensory stimuli.

³Hyperalgesia is increased sensitivity to nociceptive stimuli.

⁴Hypoalgesia is decreased sensitivity to nociceptive stimuli.

⁵Allodynia is feeling pain in response to non-nociceptive stimuli.

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