A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome

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Abstract

Objective

Although the term ‘reflex sympathetic dystrophy’ has been replaced by ‘complex regional pain syndrome’ (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain [“sympathetically maintained pain” (SMP)], even in the absence of detectable neuropathophysiology.

Methods

We have used microneurography to evaluate possible electrophysiological interactions in 24 patients diagnosed with CRPS I (n = 13), or CRPS II (n = 11) by simultaneously recording from single identified sympathetic efferent fibers and C nociceptors, while provoking sympathetic neural discharges in cutaneous nerves.

Results

We assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors, recorded in CRPS I (26 nociceptors) and CRPS II patients (28 nociceptors). No evidence of activation of nociceptors related to sympathetic discharge was found, although nociceptors in six CRPS II patients exhibited unrelated spontaneous pathological nerve impulse activity.

Conclusions

We conclude that activation of nociceptors by sympathetic efferent discharges is not a cardinal pathogenic event in either CRPS I or CRPS II patients.

Significance

This study shows that sympathetic–nociceptor interactions, if they exist in patients communicating chronic neuropathic pain, must be the exception.

Introduction

Historically it has been assumed that the sympathetic nervous system plays a pathogenic role in some chronic pain conditions, variously labeled RSD (reflex sympathetic dystrophy), SMP (sympathetically maintained pain) or CRPS (complex regional pain syndrome) (Ochoa and Verdugo, 1993), largely on the grounds of physical signs commonly regarded as autonomic, and of subjective symptom relief following sympatholysis (Loh and Nathan, 1978). The presumptive site of interaction between the sympathetic efferent fibers and the afferent system has shifted over time, from the nerve trunk (Nathan, 1947), to the nociceptor terminal (Hannington-Kiff, 1974, Loh and Nathan, 1978, Sato and Perl, 1991, Gibbs et al., 2008), to low threshold mechanoreceptors (Roberts, 1986), and to the dorsal root ganglion (Michaelis et al., 1996). An abnormal state of excitability in the dorsal horn, triggered or maintained by sympathetic activity, has also been postulated (Evans, 1946).

In animals, several studies have investigated possible sympathetic–nociceptor interactions following experimental nerve damage. Roberts and Elardo (1985) reported that electrical stimulation of the sympathetic chain in cats might activate Aδ nociceptor afferents after experimental inflammation. Also, following nerve injury in animals, nociceptor terminals may develop sensitivity to catecholamines, and become excitable during sympathetic stimulation (Häbler et al., 1987, Sato and Perl, 1991, Jänig et al., 1996, O’Halloran and Perl, 1997, Birder and Perl, 1999). According to Ren et al. (2005) sensitization of cutaneous Aδ and C nociceptors by capsaicin was prevented by sympathectomy and rekindled by adrenergic agonists. In a previous report, however, sympathectomy did not prevent discharge of chemically sensitized afferents (Koltzenburg et al., 1992).

In behavioral studies in human volunteers, the capsaicin-evoked pain and mechanical hyperalgesia remained unchanged during full body warming or cooling, maneuvers known to decrease and increase maximally the sympathetic vasoconstrictor tone (Baron et al., 1999). Moreover, in volunteers, mechano-insensitive C nociceptors, sensitized by capsaicin and tested through microneurography, were not responsive to sympathetic reflex maneuvers (Serra et al., 2004). Furthermore, the putative abnormal interaction between sympathetic efferent activity and afferent activity in human polymodal nociceptors sensitized with mustard oil has also been addressed through microneurography with negative results (Elam et al., 1999).

In chronic pain patients with or without demonstrable nerve damage, psychophysical studies led to the assumption that sympathetic efferent activity is a significant determinant of the pains. Indeed, diagnostic and therapeutic sympathetic blocks are often followed by transient symptom relief, although this effect has been attributed directly to placebo (Verdugo and Ochoa, 1994, Verdugo et al., 1994, Jadad et al., 1995, Ramamurthy and Hoffman, 1995). Conversely, there are examples where exogenous norepinephrine might trigger a pain complaint. An injection of norepinephrine near a stump neuroma in amputees reportedly evoked significant pain (Chabal et al., 1992). Further, norepinephrine injected in previously symptomatic skin of patients diagnosed with SMP, neuralgia or causalgia, was reported to rekindle the symptom (Wallin et al., 1976, Torebjörk et al., 1995). Ali et al. (2000) reported that norepinephrine injections produced pain in SMP patients at doses that were just at the threshold for producing vasoconstriction. Mailis-Gagnon and Bennett (2004) describe enhanced pain responses to intradermal norepinephrine in asymptomatic skin in patients with SMP and suggest a central rather than a peripheral mechanism for this phenomenon. All these claims are based upon subjective self-reports.

In fact, no pathologically increased sympathetic neuro-secretion to symptomatic areas has been documented in patients labeled with RSD (Goldstein et al., 2000) and sympathetic efferent neural activity is not abnormally increased in patients assessed with SMP (Elam, 1998). However, a recent case report (Jørum et al., 2007) described a patient with a chronic pain condition in whom spontaneous activity recorded by microneurography from skin nociceptor units was enhanced by maneuvers that normally increase sympathetic outflow. Further direct neurophysiological studies in patients therefore seemed warranted.

Here, we present a series of 24 patients with complex regional pain syndromes type I and II (CRPS I and II, without and with nerve injury, respectively) in whom we searched, through the use of microneurography, for potential interactions between natural sympathetic activity documented for individual efferent fibers and afferent activity in subtype-identified nociceptors innervating symptomatic areas. No evidence of interaction was found for either polymodal or mechanically-insensitive C fiber nociceptors in these patients.

Section snippets

Subjects

All subjects (24 patients and 1 healthy volunteer) gave informed written consent to be studied; the consent form was approved by the Legacy System and Universidad del Desarrollo local ethics committees.

Thirteen consecutive patients fulfilling diagnostic criteria for CRPS I (Merskey and Bogduk, 1994) (see Section 4) were included, as well as 11 patients with CRPS II, of which 10 had painful neuropathy and 1 a traumatic nerve injury. Patients reporting chronic pain associated with motor and

Clinical aspects

Twenty-four patients (Table 1) that fulfilled the diagnosis of CRPS (13 CRPS I and 11 CRPS II) underwent successfully one or more microneurography recordings. Mean age of CRPS I patients (8 females, 5 males) was 40.2 years, slightly younger than the CRPS II patients (4 females, 7 males) (mean age 44.5 years). All patients communicated spontaneous pain and various degrees of static or dynamic mechanical hyperalgesias. Their main clinical features are summarized in Table 1. The sensory symptoms of

Discussion

Our search for abnormal excitation of single identified CMH and mechano-insensitive nociceptor afferents, induced by documented sympathetic efferent activation in symptomatic painful limbs of 24 patients fitting the descriptive categories CRPS I and CRPS II (Merskey and Bogduk, 1994), has been negative. The present results differ from those in a single case study that also used microneurography (Jørum et al., 2007, Ochoa, 2007). In all 24 CRPS patients we have failed to detect any evidence of

Conclusions

In 13 CRPS I and 11 CRPS II patients we could find no electrophysiological single nerve fiber evidence for activation of C nociceptors related to efferent activity in sympathetic efferent fibers. Therefore an a priori supposition of sympathetic involvement in pain generation at the C nociceptor level in either CRPS I or CRPS II is likely to be unfounded and may distract attention away from potentially treatable mechanisms.

Acknowledgment

This work was supported by NIH Grant R01-NS48932. The authors do not have conflicts of financial interests, and there are no sponsors from the industry.

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