In the following section, the results of this review will be described, structured according to the modes of assessment. We would like to note that although terms like ‘pain thresholds’ and ‘pain detection thresholds’ are used mutual in the reviewed literature, they have the same meaning. To avoid confusion, we will use the term ‘pain threshold’ in this review, which is defined by the International Association of Pain (Merskey and Bogduk, 1994) as the least experience of pain which a subject can recognize. In addition, we will use the terms ‘pain tolerance threshold’, which has been defined as the greatest level of pain that a subject is prepared to tolerate, and ‘perception threshold’ to describe the first sensation perceived by a subject.
3.4.1 Mechanical stimuli
18.104.22.168 Deep tissue stimulation
Pressure algometry involves applying mechanical stimuli and is the most commonly used psychophysical quantitative technique to assess pain in myofascial tissues and joints (Fischer and Russell, 1998). A reduction in pressure pain thresholds or increased pain ratings at the area of injury indicates the presence of primary hyperalgesia. But when pressure pain thresholds or increased pain ratings are also detected at remote, asymptomatic sites, this indicates the presence of widespread hyperalgesia, a clinical manifestation of central sensitization. Pressure algometry was used as one of the outcome measures in 16 of the 22 studies (Kasch et al., 2001, 2005; Sterling et al., 2003, 2008, 2010; Banic et al., 2004; Herren-Gerber et al., 2004; Lemming et al., 2005; Scott et al., 2005; Chien et al., 2008, 2009, 2010; Gerdle et al., 2008; Schneider et al., 2010; Sterling, 2010; Kamper et al., 2011). Banic et al. (2004) and Kasch et al. (2005) only assessed the pain and pain tolerance thresholds in response to pressure at local, symptomatic sites (i.e., the neck area) providing evidence for primary hyperalgesia, but not for widespread hyperalgesia and therefore could not judge central sensitization. All remaining studies assessed local, symptomatic and/or remote, asymptomatic sites and established lowered pain thresholds and/or pain tolerance thresholds in response to pressure at both sites demonstrating the presence of widespread hyperalgesia in chronic WAD (Kasch et al., 2001, 2005; Herren-Gerber et al., 2004; Lemming et al., 2005; Scott et al., 2005; Chien et al., 2008, 2009, 2010; Gerdle et al., 2008; Sterling et al., 2008; Schneider et al., 2010; Sterling, 2010; Kamper et al., 2011).
Seven prospective studies were reviewed. In a first study, Kasch et al. (2001) used manual palpation combined with pressure algometry on the neck and jaw muscles, and at a distal control site in acute WAD patients. Assessments were performed after 1 week and 1, 3 and 6 months after injury and the control group existed of patients with an acute ankle injury. Initially, WAD patients had lowered pressure pain thresholds and higher palpation scores in the neck/head, but the distal control site was not sensitized. In addition, the groups were similar after 6 months, and no evidence was found to support the presence or role of central sensitization in the development of chronic pain complaints in whiplash. However, the authors did not differentiate between recovered and non-recovered patients at the follow-up assessments. It is possible that the non-recovered patients presented with lower pressure pain thresholds but that the total effect was offset by the normalized thresholds from the recovered patient group. In a subsequent study, Kasch et al. (2005) took this into consideration. They examined 141 WAD patients, who were divided to recovered and non-recovered, and 40 ankle-injured controls. WAD patients showed a decreased pressure pain tolerance threshold at the masseter muscle 3 to 6 months after the injury when compared to controls. In comparison to recovered WAD patients, non-recovered or chronic WAD patients showed reduced pressure pain tolerance threshold at the masseter muscle 6 months after the injury and a tendency towards a reduced tolerance threshold 3 and 12 months after the injury. Because only a local site was examined, this study provides no evidence for the presence or absence of general, widespread hypersensitivity. Sterling et al. (2003) examined the pain pressure thresholds at local sites (on the neck) and distal, remote sites (on the upper and lower limbs). Local mechanical hyperalgesia was established in the cervical spine at 1 month post-injury, persisting up to 6 months post-injury in those patients who reported moderate/severe symptoms but resolved by 2 months in those who had recovered or reported persistent mild symptoms. In addition, patients with moderate/severe symptoms had lowered pain pressure thresholds at all sites 6 months post-injury, demonstrating generalized hypersensitivity. The findings were confirmed in a second study performed by Sterling (2010). In the study of Chien et al. (2010) the pain pressure thresholds were measured in order to classify whiplash to a low- or high-risk group for poor recovery; however, the authors did not examine whether the thresholds evolved over time.
Kamper et al. (2011) examined the association between pain pressure threshold measures and neck and general pain. Significant but weak associations were found, both in the acute and the chronic phases of whiplash. This finding is in line with our current understanding of central sensitization (i.e., that symptom changes, such as an increase in neck/general pain complaints, do not correspond to what happens in the tissues).
One study examined the effect of cervical spine manual therapy on pain pressure thresholds in chronic WAD. Although pain pressure thresholds at local and remote sites increased after the experimental intervention, there were no statistically significant differences when compared to the control intervention which existed of manual contact (Sterling et al., 2010).
22.214.171.124 Skin and nerve tissue stimulation
While pressure algometry can be used to examine the sensitivity of muscle tissue, the sensitivity of the skin can be examined by applying mechanical stimuli using Von Frey hairs filaments or a Wartenberg pinwheel. Von Frey testing was used to assess low-threshold mechanoreceptive function or the perception threshold to light touch and punctuate hyperalgesia at the cervical and upper brachial regions. Scott et al. (2005) did not found evidence for the presence of punctuate hyperalgesia in chronic WAD patients. However, we must consider that the authors only based these conclusions on a preliminary analysis, which was performed with part of the data (n = 20), not testing the hypothesis on the full sample size of WAD patients (n = 30). To the contrary, Kosek and Januszewska (2008) established increased perception thresholds to light touch, demonstrating a decreased sensitivity to light touch in chronic WAD patients. In addition, the authors reported that local anaesthesia did not affect these perception thresholds. The Wartenberg pinwheel was used to examine hypersensitivity in the thoracic dermatomes, and 70% of the examined chronic WAD patients presented thoracic allodynia (Bock et al., 2005).
The Brachial Plexus Provocation Test (BPPT) test involves the application of controlled longitudinal provocative stimuli, which aims to provoke the nerve tissues and to test for mechanical sensitivity of the upper limb nerve tissue (Sterling et al., 2008). The validity of the BPPT as a measure of central hyperexcitability has not been established, but hypersensitive responses to this test have been demonstrated in people with acute and chronic WAD (Ide et al., 2001; Sterling et al., 2003, 2008). Chronic WAD patients demonstrated hyperalgesic responses to the BPPT (lower elbow extension accompanied with higher pain levels during the BPPT) when compared to asymptomatic control subjects (Chien et al., 2008, 2009). Similar findings were reported by Sterling et al. (2002b), who described that the responses were bilateral and occurred in all chronic WAD subjects, regardless of whether or not the subjects reported arm pain as a symptom of their condition. Within the WAD population, subjects whose arm pain was reproduced by the BPPT demonstrated more severe hyperalgesic responses when compared to the WAD subjects whose arm pain was not reproduced by the BPPT and the WAD subjects without arm pain. The BPPT was also used in two prospective studies. In the study of Sterling et al. (2003), WAD patients with moderate/severe symptoms and patients with mild symptoms showed less range of elbow extension and reported more pain during the test than both the control group and the patients who recovered at 6 months. The authors suggested that the decreased threshold to mechanical stimulation evoked by the BPPT is a hyperalgesic sensory response, which is suggestive for the presence of central sensitization. Ferrari (2010) showed that whiplash patients their expectations of recovery in the acute phase can be predictive of the results on the BBPT in the chronic phase. WAD patients with negative expectations reported more arm pain during the BPPT at 6 months follow-up.
Chien et al., 2008, 2009, 2010) also measured the vibration perception thresholds by means of a vibrometer over areas of the hand innervated by the distal aspect of the C6, C7 and C8 nerves. In these studies, chronic WAD patients demonstrated elevated perception thresholds for all sites compared to the control group. In addition, whiplash patients who have a high risk for poor recovery will demonstrate higher perception thresholds to vibration that patients with a low risk (Chien et al., 2010). These findings could be important because altered vibration detection sense is thought to be an early indicator of neural pathology (Greening et al., 2003).
126.96.36.199 Thermal stimuli
Thermal stimuli have also been used to evaluate central sensitization in patients with chronic WAD. Using heat or cold, perception and pain thresholds can be measured. Nine research papers examined the response in chronic WAD patients to thermal stimuli. A thermode was used in 11 of the studies (Curatolo et al., 2001; Sterling et al., 2003, 2008, 2010; Scott et al., 2005; Raak and Wallin, 2006; Chien et al., 2008, 2009, 2010; Schneider et al., 2010; Sterling, 2010), while one study used the cold pressor test (Kasch et al., 2005). Eight articles reported significantly reduced cervical cold pain thresholds (Sterling et al., 2003, 2008; Scott et al., 2005; Raak and Wallin, 2006; Chien et al., 2008, 2009; Schneider et al., 2010; Sterling, 2010). When chronic WAD patients are categorized using the severity of their symptoms, these reduced cervical cold pain thresholds were only established in patients with more severe symptoms (Sterling, 2010). Three articles reported reduced cervical heat pain thresholds (Sterling et al., 2003; Scott et al., 2005; Raak and Wallin, 2006). In addition, reduced cold and heat pain thresholds were established at remote sites such as the lower limbs (Scott et al., 2005; Chien et al., 2008, 2009). Three studies reported normal heat pain thresholds (Curatolo et al., 2001; Sterling et al., 2008; Chien et al., 2009). Although Sterling et al. (2008) measured heat pain thresholds at different sites, local and remote, one mean value was reported. Therefore, we were not able to study the reactions of the different testing sites to unveil possible reasons, which might explain why no differences were found between the WAD and the control group. In addition, one study used thermal pain thresholds as one of the outcome measures to examine a therapy effect (Sterling et al., 2010). The authors found that cervical spine manual therapy was not able to alter heat or cold pain thresholds in chronic WAD patients.
Even though Chien et al. (2009) were not able to establish decreased heat pain thresholds, the authors did establish decreased heat pain perception thresholds. Heat perception thresholds were higher at the areas of the hand innervated by C6, C7 and C8 (Chien et al., 2008, 2009, 2010) and the thenar (Raak and Wallin, 2006), while cold perception thresholds were reduced in areas of the hand innervated by C8 (Chien et al., 2009). Some studies however did not find any altered cold perception thresholds in patients with chronic WAD (Raak and Wallin, 2006; Chien et al., 2008, 2010). Normal heat pain tolerance thresholds at the neck and the lower limb were established in chronic WAD patients (Curatolo et al., 2001).
Kasch et al. (2005) were interested in examining whether abnormal central pain processing could be responsible for the transition from acute to chronic WAD. Therefore, pain responses after exposure of the hand to cold water (i.e., the cold pressor test) were registered. Patients who had not recovered reported more pain and discomfort in response to the cold pressor test after the injury. In addition, these patients experienced pain earlier during the test compared to the non-recovered patients, when examined immediately after the injury and 6 months after the injury. Because this reduction in pain endurance was established immediately after the injury, it indicates that non-recovery or chronicity may be a result of altered pain processing that occurs very early after injury. In addition, using the cold pressor pain as a counter-stimulation for the induced pressure pain on the right masseter muscle allowed the authors to asses diffuse noxious inhibitory controls (DNIC) functioning. The DNIC, which acts as a filter separating irrelevant stimuli from relevant stimuli, is an important pain inhibitory mechanism used by the human body to modulate pain. DNIC occurs when the response (i.e., pain perception) to a noxious stimulus is inhibited by a second, spatially remote noxious stimulus. Although DNIC seemed to be impaired in chronic WAD patients 6 months after the injury, normal DNIC activation was established in the non-recovered WAD patients.
188.8.131.52 Electrical stimuli
In 10 studies, electrical stimulation was used to evaluate central sensitization in patients with chronic WAD (Curatolo et al., 2001; Banic et al., 2004; Lemming et al., 2005; Chien et al., 2008, 2009, 2010; Kosek and Januszewska, 2008; Sterling et al., 2008, 2010; Sterling, 2010). Electrical stimulation bypasses peripheral receptors and when pain hypersensitivity is observed after stimulation of uninjured body parts evidence is provided for the involvement of central pain mechanisms (Handwerker and Kobal, 1993). The nociceptive withdrawal reflex is a spinal reflex, which can be evoked from the lower limb (nociceptive flexion reflex) by single or repeated (temporal summation) electrical stimulation and allows us to assess the excitability of spinal neurons. In the studies of Banic et al. (2004), Sterling (2010) and Sterling et al. (2008, 2010), the nociceptive withdrawal reflex threshold responses to single electrical stimulation on the sural nerve were registered using EMG. The stimulus intensity necessary to evoke a spinal reflex was significantly lower in patients with chronic WAD than in healthy subjects (Banic et al., 2004; Sterling et al., 2008), which demonstrates a state of hypersensitivity of spinal neurons to peripheral stimulation in these patients. Sterling (2010) found that the nociceptive withdrawal reflex threshold were decreased in the acute phase unregarded patients their symptom severity. However, in the chronic phase, only patients with moderate to severe symptoms presented decreased nociceptive withdrawal reflex thresholds. Sterling et al. (2008) found no relationships between psychological factors and the nociceptive flexion reflex responses. The authors were able to demonstrate that cervical spine manual therapy can be used to increase nociceptive flexion reflex thresholds measured in the lower limb sites (Sterling et al., 2010). However, pain ratings during the test did not change. These findings suggest that cervical spine manual therapy could be used to influence nociceptive processing and to modulate spinal cord hyperexcitability.
Temporal summation or wind-up occurs when repeated stimuli of constant intensity evoke an increase in the intensity of perception during repeated stimulation, so that the latter stimuli are perceived as painful (Price, 1972). The pain evoked by temporal summation is believed to result from a temporary hyperexcitability of spinal cord neurons (wind-up), a process that probably contributes to central sensitization (Mendell and Wall, 1965; Mendell, 1966). The efficacy of temporal summation of pain can be assessed by measuring pain thresholds during repetitive electrical stimulation. Curatolo et al. (2001) established decreased pain thresholds or hypersensitivity at the neck and the lower limb sites in response to single and repeated intramuscular, and repeated transcutaneous electrical stimulation. Lemming et al. (2005) reported that intramuscular and cutaneous pain thresholds at the lower limbs of chronic WAD patients were significantly lower in response to repeated electrical stimulation compared to single stimulation. In these studies, central hypersensitivity was demonstrated as it is clear that when pain hypersensitivity is observed after electrical stimulation of healthy areas, it is caused by hyperexcitability of the central nervous system. The facilitated temporal summation, which was established in chronic whiplash patients, further supports this theory.
Electrical detection thresholds were studied by Chien et al., 2008, 2009, 2010). The electrical detection threshold is calculated as the mean of the perception and the disappearance threshold. Chien et al., 2008, 2009, 2010) established elevated electrical detection thresholds, which demonstrated the presence of hypoaesthesia at the upper limb sites but not at the lower limb sites. When the authors accounted for the prospect of recovery, they found that a high risk of poor recovery was predictive for increased electrical detection thresholds at distal sites, i.e., the index finger (Chien et al., 2010). Although it was examined whether elevated levels of somatization, depression and psychological depression in chronic WAD patients had an influence on any of the outcomes, no differences were established (Chien et al., 2008).
This hypoesthesia to light touch and electrical current reported by Chien et al., 2008, 2009, 2010) reminds us of the numbness in the referred pain area, which is often reported by chronic WAD patients in the clinical practice. And because hypoesthesia has not been reported in asymptomatic and remote areas, but rather in symptomatic and referred pain areas, it has been suggested that prolonged nociceptive input may have an inhibitory effect on the perception of touch (Chien et al., 2008; Kosek and Januszewska, 2008).
Kosek and Januszewska (2008) investigated pain referral in patients with chronic WAD using intramuscular electrical stimulation. Chronic WAD patients showed increased sensitivity to noxious intramuscular stimulation and required lower intensities of conditioning stimulation to induce referred pain. During the same subjectively painful conditioning stimulation, chronic WAD patients’ perceived referred pain was more frequently induced and spread to larger areas compared to healthy subjects. In addition, WAD patients reported proximal referral of pain, which was never perceived by the healthy subjects. Because chronic WAD patients reported an abnormally increased spread of pain during the same subjectively painful stimulation as used in healthy subjects, this study provided evidence for altered central nervous system processing of nociceptive input in whiplash.
184.108.40.206 Injection of local anaesthetics
Local injections with mediators such as local anaesthetics or hypertonic saline can be used to examine the role of nociceptive input and the association with symptoms and central hypersensitivity, and to investigate referred pain, a central phenomena that is of clinical relevance. Curatolo et al. (2001) used an injection of a local anaesthetic into tender and painful muscles of the neck to examine the role of nociceptive input. Local anaesthesia did not influence pain thresholds or hypersensitivity at the neck and the lower limb sites in response to single and repeated intramuscular and transcutaneous electrical stimulation, nor did it influence neck pain intensity. These study results suggest that generalized hypersensitivity is not dependent on nociceptive input arising from the painful and tender muscles. Herren-Gerber et al. (2004) also injected a local anaesthetic into tender and painful muscles of the neck and expected an increase in the pain thresholds measured at the injected point and decreased neck pain. However, they observed both a decrease in pain thresholds and an increase in neck pain. This was a local effect, as no change was detected at the remote testing site (i.e., the second ipsilateral toe). The authors proposed that injection and infiltration produced a local transient trauma with peripheral and central sensitization that increased neck pain and decreased pain pressure thresholds. It seemed likely that the painful and tender points were areas of referred pain, and these findings suggest that the underlying mechanisms of hyperalgesia at areas surrounding the site of injury are different from the ones that determine generalized hyperalgesia to distant body areas. Instead of influencing the nociceptive input of the muscles, Schneider et al. (2010) anaesthetically blocked the nociceptive input from the zygapophyseal joints. Consequently, the elevated cold pain thresholds in the neck decreased and the decreased pain pressure thresholds increased at local and remote sites (i.e., neck, upper and lower limbs), which suggests that nociceptive input arising from the zygapophyseal joints has an influence generalized hypersensitivity in chronic WAD.
In another study, some chronic WAD patients reported widespread areas of referred pain with proximal spread, after infusion of hypertonic saline into the tibialis anterior muscle (Lemming et al., 2005). In addition, the authors examined the response to intravenous treatment with morphine, lidocaine, ketamine and a placebo. The pharmacological drugs had short-term analgesic effects (up to 120 min after administration) on general pain and neck pain intensity. Although subgroups of patients with chronic WAD were identified based on treatment response, the authors were unable to identify the cause of this differentiation. Nevertheless, they considered the role of different pain processing mechanisms and dysfunctions of nociceptive pathways in chronic WAD as the basis for the differentiation. The pattern of response to the pharmacological challenges did not show any clear relationships with pain duration or the experimental pain tests.
220.127.116.11 Sympathetic vasoconstrictor reflex
To examine the involvement of the sympathetic nervous system in the symptoms of chronic WAD, the sympathetic vasoconstrictor reflex has been measured using laser Doppler flowmetry during a provocation manoeuvre (i.e., an inspiratory gasp). Sterling et al. (2003) found that WAD patients with moderate/severe symptoms showed a tendency for diminished sympathetic reactivity 6 months post-injury, although these effects were not statistically significant. Chien et al. (2009), however, compared the results of chronic WAD patients and healthy people, and demonstrated reduced vasoconstriction in the chronic WAD group.