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Pain elicited by blunt pressure: neurobiological basis and clinical relevance
Pain 98 (2002) 235–240 www.elsevier.com/locate/pain
Topical review
Pain elicited by blunt pressure: neurobiological basis and clinical relevance R.-D. Treede a,*, R. Rolke a, K. Andrews b, W. Magerl a a
Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Saarstrasse 21, D-55099 Mainz, Germany b Department of Anatomy and Developmental Biology, University College, London, UK Received 3 June 2002; accepted 4 June 2002
Keywords: Nociception; Muscle; Tendon; Periosteum; Quantitative sensory testing
1. Introduction Polymodality is one of the distinguishing features of primary nociceptive afferents, meaning that these free nerve endings respond to mechanical, thermal and chemical stimuli (Raja et al., 1999). Tissue damage has originally been suggested to be the common denominator of these adequate stimuli. This concept is still important for terminology in terms like ‘noxious stimulus’ and ‘nociceptive system’, but outright damage is not necessary for the activation of most nociceptors. The molecular cloning of the capsaicin receptor VR1 (now called TRPV1) has unified two stimulus modalities as adequate activators of one specific signal transduction pathway (for noxious heat and for irritant substances of the vanilloid class). Noxious mechanical stimuli are encoded by mechanisms different from this signal transduction pathway, but these mechanisms have not been characterized yet. Mechanically evoked pain is important both for the enteroceptive and the exteroceptive aspects of pain perception. Tension or spasms in visceral organs, joint or muscle movements, and increased pressure within the tooth pulp or the bone marrow are important adequate stimuli to elicit visceral or deep somatic pain. These stimuli inform the nervous system about the inner state of the organism (enteroception). On the other hand, the exertion of pressure onto the skin from the outside gives information about impending injury (exteroception). Pressure that is exerted onto the skin may activate nociceptive afferents in several tissues, depending on the configuration of the object that exerts the pressure (Fig. 1).
* Corresponding author. Tel.: 149-6131-3925715; fax: 149-61313925902. E-mail address: [email protected] (R.-D. Treede).
Contact with a punctate object such as a 0.2 mm diameter needle may exclusively activate intraepidermal nerve endings. Because deformation of the thin epidermis can be achieved with very small forces (Garnsworthy et al., 1988; Garell et al., 1996), these stimuli have little effect on afferents in deeper tissues. In contrast, a preferential activation of deep afferents is possible, if pressure is exerted on a large skin area (e.g. 1 cm 2) and the contact surface is rounded or padded. According to experiments using topical local anaesthesia, the contribution of cutaneous afferents to pain evoked by blunt pressure is minor (Kosek et al., 1995). The aim of this topical review is to outline where an altered sensitivity to blunt pressure that presumably activates nociceptors in deep tissues is clinically relevant. In addition, we will discuss the potential neural mechanisms of mechanically-induced pain. 2. Fibromyalgia and myofascial pain According to the criteria of the American College of Rheumatology, fibromyalgia (FM) is defined by chronic diffuse musculoskeletal pain and a low mechanical pain threshold at so-called tender points (Wolfe et al., 1990). Pain threshold at these tender points is usually assessed by palpation, and tender point counts are used pragmatically for patient classification. Pressure pain thresholds in FM patients have been measured with calibrated devices (Tunks et al., 1988; Granges and Littlejohn, 1993; Lautenbacher et al., 1994; Kosek et al., 1995). Lowered pressure pain threshold at tender points has been illustrated in these studies, but several findings suggest that FM is characterized by a more generalized increase in pain sensitivity: pressure pain threshold in FM patients was also lowered in areas not designated as tender points, and pain sensitivity was also enhanced for heat and for electrical stimuli.
0304-3959/02/$20.00 q 2002 International Assocaition for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S 0304-395 9(02)00203-8
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Fig. 1. Differential effects of punctate or blunt pressure to the skin. In this schematic drawing, the thickness of the epidermis has been exaggerated; the epidermis measures about 40–80 mm, except on the palmar side of the hand and the plantar side of the feet. (A) Contact with a punctate probe that has pronounced contours, e.g. the tip of a needle or a small flat cylinder (Magerl et al., 2001), causes a strong deformation within the epidermis. The epidermis is densely innervated by free nerve endings of A- and C-fibre nociceptors. If the punctate probe is small enough, nociceptive afferents can be activated by extremely low forces (e.g. 1 mN, Garnsworthy et al., 1988), which do not cause deformations of deeper tissue. (B) Contact with a large blunt probe induces deformations in both epidermis and deeper tissue. The larger the probe size, the more force is needed to activate the intraepidermal afferents (Garell et al., 1996). As a consequence, the deformation reaches deeper layers such as the dermis, muscle or periosteum. Rounded or cushioned tips minimize the deformation in the epidermis, and may enable a preferential activation of deep afferents. For selective activation of deep afferents, the epidermis should be anaesthetized, e.g. using EMLA cream (Kosek et al., 1995).
The aetiology and the pathophysiological mechanisms of FM are unknown. It has been suggested that the widespread pain and tenderness in FM are consequences of a dysfunction of central pathways involved in pain modulation (Mense, 2000). Descending pain modulatory pathways can be inhibitory as well as excitatory (Ren et al., 2000), and either reduced activity in the former or increased activity in the latter could lead to generalized pain of the kind that is seen in FM. In healthy subjects, pressure pain threshold was also lower at a designated tender point than at a control point (Lautenbacher et al., 1994). The type of tissue, however, that is responsible for the pronounced mechanical pain sensitivity at tender points is controversial. In addition to tendon insertion points, the muscle itself as well as nearby nerves have been suggested. Cutaneous afferents do not seem to be involved, since tenderness was not affected by topical anaesthesia of the skin (Kosek et al., 1995). In contrast to FM, myofascial pain is defined as a local or regional musculoskeletal pain, that is characterized by painful trigger points (Simons and Mense, 1998). Pressure onto a trigger point elicits both local and referred pain. Trigger points may be palpable as taut bands that are thought to be due to localized contractures in the motor endplate region (Mense, 1999). By their distinct definitions, myofascial pain can be distinguished from FM, but both conditions may occur in the same patient.
3. Temporomandibular disorder Temporomandibular disorder (TMD) of myogenous origin is characterized by pain in the masseter or temporal area associated with a history of masticatory dysfunction, but without a dysfunction of the temporomandibular joint (Dworkin and LeResche, 1992). Muscle tenderness of masseter and temporalis muscles is a salient feature of this disorder, and pressure pain threshold measurement has demonstrated reliability and validity as a diagnostic tool
in this condition (Ohrbach and Gale, 1989; Farella et al., 2000). In both of these studies, the reliability of pressure pain threshold measures was shown to be greater than the reliability of other signs and site-specific symptoms. The positive predictive value of pressure pain thresholds has been reported as 68% for the masseter muscle and 74% for the temporalis muscle (Farella et al., 2000). Pressure pain threshold reliability was superior also to other methods in the diagnosis of this condition, including thermal threshold measurement (Svensson et al., 2001). Reduced pressure pain thresholds have been demonstrated on the painful side in masticatory muscles of patients with TMD (Ohrbach and Gale, 1989; Farella et al., 2000), being significantly lower here than at the non-painful contralateral muscle. The localized tenderness is further confirmed by the finding that local changes in the form of palpable bands and nodular areas are most commonly associated with muscle regions that produce pain in TMD patients (Ohrbach and Gale, 1989). However, significantly reduced pressure pain thresholds compared with control subjects have also been shown in the same muscles on the contralateral, non-painful side and in remote muscles in these patients (Ohrbach and Gale, 1989; Farella et al., 2000; Svensson et al., 2001), suggesting that more generalized, probably central mechanisms also play a part in pain experienced in this condition. The local tenderness of the masticatory muscles in patients with TMD is considered to be equivalent to myofascial pain in other locations. The hypersensitivity in remote muscles may appear to be similar to FM, but patients with TMD do not normally fulfil the diagnostic criteria of FM (Svensson et al., 2001).
4. Tension-type headache According to the IHS criteria (Headache Classification Committee of the International Headache Society, 1988) tension-type headache (TTH) can be described as pain of
R.-D. Treede et al. / Pain 98 (2002) 235–240
mild or moderate intensity with a pressing or tightening quality of bilateral location and no aggravation by routine physical activity. Both episodic and chronic TTH are often associated with tenderness of pericranial muscles. To document such pericranial muscle disorders, manual palpation, EMG recordings, and electronic or conventional hand-held algometers are recommended (IHS criteria). Compared with healthy control subjects, patients with TTH exhibited tenderness and decreased pressure pain thresholds in several pericranial muscles (Langemark and Olesen, 1987; Bendtsen et al., 1996; Schoenen et al., 1991). This localized tenderness was taken as evidence for an initiating peripheral source of pain, possibly due to primary sensitization of peripheral myofascial nociceptors. The same studies, however, also revealed enhanced mechanical pain sensitivity at remote sites such as the fingers or the Achilles tendon. The widespread hypersensitivity was interpreted to indicate sensitization of the central nervous system as well as impairment of central antinociceptive systems. Whereas determination of trigger points and pericranial tenderness scores are well established clinical instruments, the clinical value of quantitative determinations of pressure pain thresholds in TTH is less clear. When compared with normal subjects, threshold abnormalities at standard predefined locations, e.g. the anterior part of the temporalis muscle, are often minor (Schoenen et al., 1991). The large number of pericranial muscles that may exhibit enhanced sensitivity precludes quantitative measurements at all sites. While testing at the most sensitive spot appears intuitively reasonable, such a procedure will introduce a selection bias. An alternative approach is suggested by findings on alterations of stimulus-response functions of pressure pain in patients with TTH (Bendtsen et al., 1996): while these functions exhibited a marked upward shift in rated pain intensity, the threshold was shifted only marginally. This finding suggests that suprathreshold testing may be more sensitive than threshold measurements.
5. Neurobiological mechanisms of pain and tenderness The majority of cutaneous primary nociceptive afferents recorded in animals and in humans are capable of signalling noxious mechanical stimuli and discriminating stimulus intensity (Leem et al., 1993; Raja et al., 1999). Most polymodal nociceptors have excitation thresholds well below the pain threshold and exhibit prominent adaptation within a few seconds of stimulation, whereas the pain from noxious pressure typically increases with long-lasting stimuli (Adriaensen et al., 1984; Magerl et al., 1990). This paradox may be explained by recruitment of initially unresponsive afferent fibres or fibre branches (mechanically insensitive or silent nociceptors) that become excitable only after longlasting stimulation (Meyer et al., 1991; Schmidt et al., 2000). Muscle, tendon and joint afferents are also slowly
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adapting to mechanical stimuli (Simone et al., 1994; Schaible and Grubb, 1993). Also for deep afferents, adaptation may be partly compensated by recruitment of silent nociceptors. Mechanosensitivity is the most important criterion to classify response properties of nociceptive neurons in the central nervous system, e.g. the dorsal horn of the spinal cord (Willis, 1985). Class 1 or low threshold neurons (LT) respond to weak mechanical stimuli with response saturation below the noxious range. Class 2 or wide dynamic range neurons (WDR) also respond to weak mechanical stimuli, but they encode stimulus intensity throughout the noxious range. Class 3 or high threshold neurons (HT) respond only to noxious mechanical stimuli. Both HT and WDR dorsal horn neurons signal input from primary afferents to blunt pressure stimuli. Notably, the discharge of spinal neurons, which reflects the integrated response of all primary afferent populations, can also not sufficiently explain the slow summation of pressure-induced pain (Cervero et al., 1988), which leaves a hitherto undefined role for supraspinal thalamic or cortical relays. Tenderness to blunt pressure may be due to peripheral sensitization of primary afferents or to central sensitization, e.g. in the spinal cord. Peripheral sensitization has been studied extensively for cutaneous afferents, where it remains strictly localized to the site of injury and is most pronounced for heat stimuli (Treede et al., 1992). Central sensitization leads to enlargement of mechanical receptive fields, which may explain some local spreading of tenderness, but widespread or generalized tenderness is more likely to be due to alterations in descending pathways from the brainstem (Ren et al., 2000).
6. Neurogenic hyperalgesia and neuropathic pain The clinical syndromes mentioned above are characterized by enhanced sensitivity to pain induced by blunt pressure. Exaggerated pain sensitivity to mechanical stimuli is also a hallmark sign of other hyperalgesia syndromes, including primary and secondary hyperalgesia following injury, postoperative pain and neuropathic pain. Experimental studies of primary and secondary hyperalgesia suggest that there are several different mechanical hyperalgesias characterized by their location and primary afferent fibres involved (Kilo et al., 1994; Treede and Magerl, 2000). Hyperalgesia to blunt mechanical stimuli appears to be based on peripheral sensitization of C-fibre nociceptors (Kilo et al., 1994). This type of mechanical hyperalgesia is confined to a site of tissue injury (primary hyperalgesia). A contribution of A-fibre nociceptors or of central sensitization has not yet been demonstrated. Hyperalgesia to punctate mechanical stimuli appears to be based on central sensitization to A-fibre nociceptor input (Ziegler et al., 1999; Magerl et al., 2001). This type of mechanical hyperalgesia occurs not only in injured tissue, but also in adjacent
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uninjured tissue (secondary hyperalgesia). Secondary hyperalgesia is characterized by pain to light touch and hyperalgesia to punctate stimuli, but not to blunt pressure (LaMotte et al., 1991; Kilo et al., 1994). Pain to light touch (allodynia) appears to be mediated by central sensitization to the input from non-nociceptive Ab-fibre afferents (Torebjo¨ rk et al., 1992). Neurogenic hyperalgesia in neuropathic pain has many characteristics in common with secondary hyperalgesia following injury (Treede et al., 1992). Hyperalgesia to punctate stimuli and to light touch are frequent symptoms in neuropathic pain. Hyperalgesia to blunt pressure has not been assessed regularly in these diseases. Some authors have suggested that it may be present, e.g. when tested over bone (Mailis et al., 1997), whereas other authors have found no evidence for hyperalgesia to blunt pressure on skin folds (Sieweke et al., 1999). It seems that these phenomena deserve further studies, e.g. as part of standard quantitative sensory testing in neuropathic pain patients.
7. Assessment The pressure pain threshold at tender or trigger points is assessed clinically by palpation with the examiner’s thumb. Evidently, this technique is subject to observer bias, systematic inter-rater differences, and other sources of variance. Although these problems are genuinely similar to those in routine clinical reflex testing, several attempts have been made at improving objectivity and reliability of pressure pain threshold testing. Some attempts have mimicked the clinical examination technique by placing a force transducer and a standardized contact surface between the examiner’s thumb and the patient’s skin (Tunks et al., 1988). Quantitative measurement of pain due to blunt pressure, whether to determine threshold or to observe stimulusresponse functions, is performed most commonly using pressure algometry with the aid of a hand-held device. The hand-held devices most often used for these purposes are the Pressure Threshold Meter (Pain Diagnostics and Thermography, Great Neck, NY) and the pressure pain Algometer (Somedic, Ho¨ rby, Sweden). Both devices have a circular rubber pad of 1 cm 2 for contact with the skin. Therefore, the different readouts may easily be transformed from one device to the other. Threshold values in ‘normal’ muscles, at myofascial trigger points, and at ‘tender spots’ have been published (Fischer, 1987; Brennum et al., 1989; Granges and Littlejohn, 1993; Kosek et al., 1995; Farella et al., 2000; Svensson et al., 2001). The Somedic Algometer provides the examiner with a feedback of the rate of manually applied pressure change. There is no standard for the rate of pressure change, which varied from 20 kPa/s (Farella et al., 2000) to 100 kPa/s (Granges and Littlejohn, 1993). This makes comparisons across studies difficult, since the
rate of force application affects the threshold of a response (Linden and Millar, 1988). While hand-held algometry is a widely used technique for examination of pain thresholds, assessment of pressure pain stimulus-response functions is rather difficult due to the problem of manually applying a constant ramp of increasing pressure. Therefore, several more complicated devices were developed that allow the application of defined suprathreshold stimuli, e.g. a skin fold squeezer (Adriaensen et al., 1984), a computerized electromechanical stimulator with controlled force and displacement in three dimensions (Schneider et al., 1995), and a computer-controlled pneumatic cuff for the lower leg (Polianskis et al., 2001). These devices have not yet been used clinically.
8. Conclusions and future research directions Pain elicited by blunt pressure plays an important role in the diagnosis of several musculoskeletal pain syndromes. Hyperalgesia to these stimuli may be grouped into two different phenomena: trigger points and tender points. Trigger points are hallmark signs of several myofascial pain syndromes including TTH and TMD. Pressure onto a trigger point may elicit both a local muscle pain and a distant referred pain. There is some evidence for a role of both local tissue factors and spinal cord neural mechanisms in trigger point pain. Tender points are the backbone of classification criteria for the diagnosis of FM. Pressure onto a tender point elicits a local pain sensation, but hyperalgesia in FM patients is neither limited to tender points nor to mechanical stimuli alone. Therefore, current hypotheses on the mechanisms of FM focus on alterations in descending control systems from the brainstem. To test the sensitivity to blunt pressure may not only be important in musculoskeletal pain disorders but also in low back pain (Clauw et al., 1999) or in neuropathic pain (Mailis et al., 1997). So far, the predictive value of quantitative testing of pressure pain in clinical studies did not consistently exceed that of clinical criteria. This mixed success may be explained by the fact that quantitative studies were mostly limited to threshold determinations, whereas clinical criteria use suprathreshold stimuli. Therefore, pain ratings to suprathreshold stimuli should become part of the repertoire of testing pain elicited by blunt pressure. Enhanced pain sensitivity to blunt pressure is attributed to hyperalgesia of deep tissues (e.g. muscle or tendon insertion points). Work on the neurobiology of pain has traditionally focussed on the innervation of the skin, whereas knowledge on deep somatic and visceral pain has accumulated considerably later. Future research efforts in the basic sciences should be particularly directed to the correlations of neurobiology and psychophysics of pain from deep somatic structures (muscle, tendon, joint, periosteum, bone). Meanwhile, research in the clinical sciences may exploit the currently available tools that allow specific
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studies on the hypothetical mechanisms of trigger points and tender points (e.g. differential local anaesthesia and quantitative sensory testing). The results of such quantitative clinical studies will be important to define those phenomena that neurobiological mechanisms of deep somatic pain are expected to explain. Acknowledgements This study was supported by the German Ministry for Education and Research (BMBF grant 01EM0107). References Adriaensen H, Gybels J, Handwerker HO, van Hees J. Nociceptor discharges and sensations due to prolonged noxious mechanical stimulation – a paradox. Hum Neurobiol 1984;3:53–58. Bendtsen L, Jensen R, Olesen J. Qualitatively altered nociception in chronic myofascial pain. Pain 1996;65:259–264. Brennum J, Kjeldsen M, Jensen K, Jensen TS. Measurement of human pressure-pain thresholds on fingers and toes. Pain 1989;38:211–217. Cervero F, Handwerker HO, Laird J. Prolonged noxious mechanical stimulation of the rat’s tail. Responses and encoding properties of dorsal horn neurones. J Physiol 1988;404:419–436. Clauw DJ, Williams D, Lauerman W, Dahlman M, Aslami A, Nachemson AL, Kobrine AI, Wiesel SW. Pain sensitivity as a correlate of clinical status in individuals with chronic low back pain. Spine 1999;24:2035– 2041. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib Disord Facial Oral Pain 1992;6:301–355. Farella M, Michelotti A, Steenks MH, Romeo R, Cimino R, Bosman F. The diagnostic value of pressure algometry in myofascial pain of the jaw muscles. J Oral Rehab 2000;27:9–14. Fischer AA. Pressure algometry over normal muscles. Standard values, validity, and reproducibility of pressure threshold. Pain 1987;30:115– 126. Garell PC, McGillis SLB, Greenspan JD. Mechanical response properties of nociceptors innervating feline hairy skin. J Neurophysiol 1996;75:1177–1189. Garnsworthy RK, Gully RL, Kenins P, Mayfield RJ, Westerman RA. Identification of the physical stimulus and the neural basis of fabric-evoked prickle. J Neurophysiol 1988;59:1083–1097. Granges G, Littlejohn G. Pressure pain threshold in pain-free subjects, in patients with chronic regional pain syndromes, and in patients with fibromyalgia syndrome. Arthritis Rheum 1993;36:642–646. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(Suppl 7):1–96. Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Different patterns of hyperalgesia induced by experimental inflammation in human skin. Brain 1994;117:385–396. Kosek E, Ekholm J, Hansson P. Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue. Pain 1995;63:335–339. LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 1991;66:190–211. Langemark M, Olesen J. Pericranial tenderness in tension headache. Cephalalgia 1987;7:249–255. Lautenbacher S, Rollman GB, McCain GA. Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain 1994;59:45–53.
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Topical review
Pain elicited by blunt pressure: neurobiological basis and clinical relevance R.-D. Treede a,*, R. Rolke a, K. Andrews b, W. Magerl a a
Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Saarstrasse 21, D-55099 Mainz, Germany b Department of Anatomy and Developmental Biology, University College, London, UK Received 3 June 2002; accepted 4 June 2002
Keywords: Nociception; Muscle; Tendon; Periosteum; Quantitative sensory testing
1. Introduction Polymodality is one of the distinguishing features of primary nociceptive afferents, meaning that these free nerve endings respond to mechanical, thermal and chemical stimuli (Raja et al., 1999). Tissue damage has originally been suggested to be the common denominator of these adequate stimuli. This concept is still important for terminology in terms like ‘noxious stimulus’ and ‘nociceptive system’, but outright damage is not necessary for the activation of most nociceptors. The molecular cloning of the capsaicin receptor VR1 (now called TRPV1) has unified two stimulus modalities as adequate activators of one specific signal transduction pathway (for noxious heat and for irritant substances of the vanilloid class). Noxious mechanical stimuli are encoded by mechanisms different from this signal transduction pathway, but these mechanisms have not been characterized yet. Mechanically evoked pain is important both for the enteroceptive and the exteroceptive aspects of pain perception. Tension or spasms in visceral organs, joint or muscle movements, and increased pressure within the tooth pulp or the bone marrow are important adequate stimuli to elicit visceral or deep somatic pain. These stimuli inform the nervous system about the inner state of the organism (enteroception). On the other hand, the exertion of pressure onto the skin from the outside gives information about impending injury (exteroception). Pressure that is exerted onto the skin may activate nociceptive afferents in several tissues, depending on the configuration of the object that exerts the pressure (Fig. 1).
* Corresponding author. Tel.: 149-6131-3925715; fax: 149-61313925902. E-mail address: [email protected] (R.-D. Treede).
Contact with a punctate object such as a 0.2 mm diameter needle may exclusively activate intraepidermal nerve endings. Because deformation of the thin epidermis can be achieved with very small forces (Garnsworthy et al., 1988; Garell et al., 1996), these stimuli have little effect on afferents in deeper tissues. In contrast, a preferential activation of deep afferents is possible, if pressure is exerted on a large skin area (e.g. 1 cm 2) and the contact surface is rounded or padded. According to experiments using topical local anaesthesia, the contribution of cutaneous afferents to pain evoked by blunt pressure is minor (Kosek et al., 1995). The aim of this topical review is to outline where an altered sensitivity to blunt pressure that presumably activates nociceptors in deep tissues is clinically relevant. In addition, we will discuss the potential neural mechanisms of mechanically-induced pain. 2. Fibromyalgia and myofascial pain According to the criteria of the American College of Rheumatology, fibromyalgia (FM) is defined by chronic diffuse musculoskeletal pain and a low mechanical pain threshold at so-called tender points (Wolfe et al., 1990). Pain threshold at these tender points is usually assessed by palpation, and tender point counts are used pragmatically for patient classification. Pressure pain thresholds in FM patients have been measured with calibrated devices (Tunks et al., 1988; Granges and Littlejohn, 1993; Lautenbacher et al., 1994; Kosek et al., 1995). Lowered pressure pain threshold at tender points has been illustrated in these studies, but several findings suggest that FM is characterized by a more generalized increase in pain sensitivity: pressure pain threshold in FM patients was also lowered in areas not designated as tender points, and pain sensitivity was also enhanced for heat and for electrical stimuli.
0304-3959/02/$20.00 q 2002 International Assocaition for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S 0304-395 9(02)00203-8
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Fig. 1. Differential effects of punctate or blunt pressure to the skin. In this schematic drawing, the thickness of the epidermis has been exaggerated; the epidermis measures about 40–80 mm, except on the palmar side of the hand and the plantar side of the feet. (A) Contact with a punctate probe that has pronounced contours, e.g. the tip of a needle or a small flat cylinder (Magerl et al., 2001), causes a strong deformation within the epidermis. The epidermis is densely innervated by free nerve endings of A- and C-fibre nociceptors. If the punctate probe is small enough, nociceptive afferents can be activated by extremely low forces (e.g. 1 mN, Garnsworthy et al., 1988), which do not cause deformations of deeper tissue. (B) Contact with a large blunt probe induces deformations in both epidermis and deeper tissue. The larger the probe size, the more force is needed to activate the intraepidermal afferents (Garell et al., 1996). As a consequence, the deformation reaches deeper layers such as the dermis, muscle or periosteum. Rounded or cushioned tips minimize the deformation in the epidermis, and may enable a preferential activation of deep afferents. For selective activation of deep afferents, the epidermis should be anaesthetized, e.g. using EMLA cream (Kosek et al., 1995).
The aetiology and the pathophysiological mechanisms of FM are unknown. It has been suggested that the widespread pain and tenderness in FM are consequences of a dysfunction of central pathways involved in pain modulation (Mense, 2000). Descending pain modulatory pathways can be inhibitory as well as excitatory (Ren et al., 2000), and either reduced activity in the former or increased activity in the latter could lead to generalized pain of the kind that is seen in FM. In healthy subjects, pressure pain threshold was also lower at a designated tender point than at a control point (Lautenbacher et al., 1994). The type of tissue, however, that is responsible for the pronounced mechanical pain sensitivity at tender points is controversial. In addition to tendon insertion points, the muscle itself as well as nearby nerves have been suggested. Cutaneous afferents do not seem to be involved, since tenderness was not affected by topical anaesthesia of the skin (Kosek et al., 1995). In contrast to FM, myofascial pain is defined as a local or regional musculoskeletal pain, that is characterized by painful trigger points (Simons and Mense, 1998). Pressure onto a trigger point elicits both local and referred pain. Trigger points may be palpable as taut bands that are thought to be due to localized contractures in the motor endplate region (Mense, 1999). By their distinct definitions, myofascial pain can be distinguished from FM, but both conditions may occur in the same patient.
3. Temporomandibular disorder Temporomandibular disorder (TMD) of myogenous origin is characterized by pain in the masseter or temporal area associated with a history of masticatory dysfunction, but without a dysfunction of the temporomandibular joint (Dworkin and LeResche, 1992). Muscle tenderness of masseter and temporalis muscles is a salient feature of this disorder, and pressure pain threshold measurement has demonstrated reliability and validity as a diagnostic tool
in this condition (Ohrbach and Gale, 1989; Farella et al., 2000). In both of these studies, the reliability of pressure pain threshold measures was shown to be greater than the reliability of other signs and site-specific symptoms. The positive predictive value of pressure pain thresholds has been reported as 68% for the masseter muscle and 74% for the temporalis muscle (Farella et al., 2000). Pressure pain threshold reliability was superior also to other methods in the diagnosis of this condition, including thermal threshold measurement (Svensson et al., 2001). Reduced pressure pain thresholds have been demonstrated on the painful side in masticatory muscles of patients with TMD (Ohrbach and Gale, 1989; Farella et al., 2000), being significantly lower here than at the non-painful contralateral muscle. The localized tenderness is further confirmed by the finding that local changes in the form of palpable bands and nodular areas are most commonly associated with muscle regions that produce pain in TMD patients (Ohrbach and Gale, 1989). However, significantly reduced pressure pain thresholds compared with control subjects have also been shown in the same muscles on the contralateral, non-painful side and in remote muscles in these patients (Ohrbach and Gale, 1989; Farella et al., 2000; Svensson et al., 2001), suggesting that more generalized, probably central mechanisms also play a part in pain experienced in this condition. The local tenderness of the masticatory muscles in patients with TMD is considered to be equivalent to myofascial pain in other locations. The hypersensitivity in remote muscles may appear to be similar to FM, but patients with TMD do not normally fulfil the diagnostic criteria of FM (Svensson et al., 2001).
4. Tension-type headache According to the IHS criteria (Headache Classification Committee of the International Headache Society, 1988) tension-type headache (TTH) can be described as pain of
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mild or moderate intensity with a pressing or tightening quality of bilateral location and no aggravation by routine physical activity. Both episodic and chronic TTH are often associated with tenderness of pericranial muscles. To document such pericranial muscle disorders, manual palpation, EMG recordings, and electronic or conventional hand-held algometers are recommended (IHS criteria). Compared with healthy control subjects, patients with TTH exhibited tenderness and decreased pressure pain thresholds in several pericranial muscles (Langemark and Olesen, 1987; Bendtsen et al., 1996; Schoenen et al., 1991). This localized tenderness was taken as evidence for an initiating peripheral source of pain, possibly due to primary sensitization of peripheral myofascial nociceptors. The same studies, however, also revealed enhanced mechanical pain sensitivity at remote sites such as the fingers or the Achilles tendon. The widespread hypersensitivity was interpreted to indicate sensitization of the central nervous system as well as impairment of central antinociceptive systems. Whereas determination of trigger points and pericranial tenderness scores are well established clinical instruments, the clinical value of quantitative determinations of pressure pain thresholds in TTH is less clear. When compared with normal subjects, threshold abnormalities at standard predefined locations, e.g. the anterior part of the temporalis muscle, are often minor (Schoenen et al., 1991). The large number of pericranial muscles that may exhibit enhanced sensitivity precludes quantitative measurements at all sites. While testing at the most sensitive spot appears intuitively reasonable, such a procedure will introduce a selection bias. An alternative approach is suggested by findings on alterations of stimulus-response functions of pressure pain in patients with TTH (Bendtsen et al., 1996): while these functions exhibited a marked upward shift in rated pain intensity, the threshold was shifted only marginally. This finding suggests that suprathreshold testing may be more sensitive than threshold measurements.
5. Neurobiological mechanisms of pain and tenderness The majority of cutaneous primary nociceptive afferents recorded in animals and in humans are capable of signalling noxious mechanical stimuli and discriminating stimulus intensity (Leem et al., 1993; Raja et al., 1999). Most polymodal nociceptors have excitation thresholds well below the pain threshold and exhibit prominent adaptation within a few seconds of stimulation, whereas the pain from noxious pressure typically increases with long-lasting stimuli (Adriaensen et al., 1984; Magerl et al., 1990). This paradox may be explained by recruitment of initially unresponsive afferent fibres or fibre branches (mechanically insensitive or silent nociceptors) that become excitable only after longlasting stimulation (Meyer et al., 1991; Schmidt et al., 2000). Muscle, tendon and joint afferents are also slowly
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adapting to mechanical stimuli (Simone et al., 1994; Schaible and Grubb, 1993). Also for deep afferents, adaptation may be partly compensated by recruitment of silent nociceptors. Mechanosensitivity is the most important criterion to classify response properties of nociceptive neurons in the central nervous system, e.g. the dorsal horn of the spinal cord (Willis, 1985). Class 1 or low threshold neurons (LT) respond to weak mechanical stimuli with response saturation below the noxious range. Class 2 or wide dynamic range neurons (WDR) also respond to weak mechanical stimuli, but they encode stimulus intensity throughout the noxious range. Class 3 or high threshold neurons (HT) respond only to noxious mechanical stimuli. Both HT and WDR dorsal horn neurons signal input from primary afferents to blunt pressure stimuli. Notably, the discharge of spinal neurons, which reflects the integrated response of all primary afferent populations, can also not sufficiently explain the slow summation of pressure-induced pain (Cervero et al., 1988), which leaves a hitherto undefined role for supraspinal thalamic or cortical relays. Tenderness to blunt pressure may be due to peripheral sensitization of primary afferents or to central sensitization, e.g. in the spinal cord. Peripheral sensitization has been studied extensively for cutaneous afferents, where it remains strictly localized to the site of injury and is most pronounced for heat stimuli (Treede et al., 1992). Central sensitization leads to enlargement of mechanical receptive fields, which may explain some local spreading of tenderness, but widespread or generalized tenderness is more likely to be due to alterations in descending pathways from the brainstem (Ren et al., 2000).
6. Neurogenic hyperalgesia and neuropathic pain The clinical syndromes mentioned above are characterized by enhanced sensitivity to pain induced by blunt pressure. Exaggerated pain sensitivity to mechanical stimuli is also a hallmark sign of other hyperalgesia syndromes, including primary and secondary hyperalgesia following injury, postoperative pain and neuropathic pain. Experimental studies of primary and secondary hyperalgesia suggest that there are several different mechanical hyperalgesias characterized by their location and primary afferent fibres involved (Kilo et al., 1994; Treede and Magerl, 2000). Hyperalgesia to blunt mechanical stimuli appears to be based on peripheral sensitization of C-fibre nociceptors (Kilo et al., 1994). This type of mechanical hyperalgesia is confined to a site of tissue injury (primary hyperalgesia). A contribution of A-fibre nociceptors or of central sensitization has not yet been demonstrated. Hyperalgesia to punctate mechanical stimuli appears to be based on central sensitization to A-fibre nociceptor input (Ziegler et al., 1999; Magerl et al., 2001). This type of mechanical hyperalgesia occurs not only in injured tissue, but also in adjacent
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uninjured tissue (secondary hyperalgesia). Secondary hyperalgesia is characterized by pain to light touch and hyperalgesia to punctate stimuli, but not to blunt pressure (LaMotte et al., 1991; Kilo et al., 1994). Pain to light touch (allodynia) appears to be mediated by central sensitization to the input from non-nociceptive Ab-fibre afferents (Torebjo¨ rk et al., 1992). Neurogenic hyperalgesia in neuropathic pain has many characteristics in common with secondary hyperalgesia following injury (Treede et al., 1992). Hyperalgesia to punctate stimuli and to light touch are frequent symptoms in neuropathic pain. Hyperalgesia to blunt pressure has not been assessed regularly in these diseases. Some authors have suggested that it may be present, e.g. when tested over bone (Mailis et al., 1997), whereas other authors have found no evidence for hyperalgesia to blunt pressure on skin folds (Sieweke et al., 1999). It seems that these phenomena deserve further studies, e.g. as part of standard quantitative sensory testing in neuropathic pain patients.
7. Assessment The pressure pain threshold at tender or trigger points is assessed clinically by palpation with the examiner’s thumb. Evidently, this technique is subject to observer bias, systematic inter-rater differences, and other sources of variance. Although these problems are genuinely similar to those in routine clinical reflex testing, several attempts have been made at improving objectivity and reliability of pressure pain threshold testing. Some attempts have mimicked the clinical examination technique by placing a force transducer and a standardized contact surface between the examiner’s thumb and the patient’s skin (Tunks et al., 1988). Quantitative measurement of pain due to blunt pressure, whether to determine threshold or to observe stimulusresponse functions, is performed most commonly using pressure algometry with the aid of a hand-held device. The hand-held devices most often used for these purposes are the Pressure Threshold Meter (Pain Diagnostics and Thermography, Great Neck, NY) and the pressure pain Algometer (Somedic, Ho¨ rby, Sweden). Both devices have a circular rubber pad of 1 cm 2 for contact with the skin. Therefore, the different readouts may easily be transformed from one device to the other. Threshold values in ‘normal’ muscles, at myofascial trigger points, and at ‘tender spots’ have been published (Fischer, 1987; Brennum et al., 1989; Granges and Littlejohn, 1993; Kosek et al., 1995; Farella et al., 2000; Svensson et al., 2001). The Somedic Algometer provides the examiner with a feedback of the rate of manually applied pressure change. There is no standard for the rate of pressure change, which varied from 20 kPa/s (Farella et al., 2000) to 100 kPa/s (Granges and Littlejohn, 1993). This makes comparisons across studies difficult, since the
rate of force application affects the threshold of a response (Linden and Millar, 1988). While hand-held algometry is a widely used technique for examination of pain thresholds, assessment of pressure pain stimulus-response functions is rather difficult due to the problem of manually applying a constant ramp of increasing pressure. Therefore, several more complicated devices were developed that allow the application of defined suprathreshold stimuli, e.g. a skin fold squeezer (Adriaensen et al., 1984), a computerized electromechanical stimulator with controlled force and displacement in three dimensions (Schneider et al., 1995), and a computer-controlled pneumatic cuff for the lower leg (Polianskis et al., 2001). These devices have not yet been used clinically.
8. Conclusions and future research directions Pain elicited by blunt pressure plays an important role in the diagnosis of several musculoskeletal pain syndromes. Hyperalgesia to these stimuli may be grouped into two different phenomena: trigger points and tender points. Trigger points are hallmark signs of several myofascial pain syndromes including TTH and TMD. Pressure onto a trigger point may elicit both a local muscle pain and a distant referred pain. There is some evidence for a role of both local tissue factors and spinal cord neural mechanisms in trigger point pain. Tender points are the backbone of classification criteria for the diagnosis of FM. Pressure onto a tender point elicits a local pain sensation, but hyperalgesia in FM patients is neither limited to tender points nor to mechanical stimuli alone. Therefore, current hypotheses on the mechanisms of FM focus on alterations in descending control systems from the brainstem. To test the sensitivity to blunt pressure may not only be important in musculoskeletal pain disorders but also in low back pain (Clauw et al., 1999) or in neuropathic pain (Mailis et al., 1997). So far, the predictive value of quantitative testing of pressure pain in clinical studies did not consistently exceed that of clinical criteria. This mixed success may be explained by the fact that quantitative studies were mostly limited to threshold determinations, whereas clinical criteria use suprathreshold stimuli. Therefore, pain ratings to suprathreshold stimuli should become part of the repertoire of testing pain elicited by blunt pressure. Enhanced pain sensitivity to blunt pressure is attributed to hyperalgesia of deep tissues (e.g. muscle or tendon insertion points). Work on the neurobiology of pain has traditionally focussed on the innervation of the skin, whereas knowledge on deep somatic and visceral pain has accumulated considerably later. Future research efforts in the basic sciences should be particularly directed to the correlations of neurobiology and psychophysics of pain from deep somatic structures (muscle, tendon, joint, periosteum, bone). Meanwhile, research in the clinical sciences may exploit the currently available tools that allow specific
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