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Endogenous Factors That Modulate Pain: Implications for Treating Fibromyalgia

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Medscape Conference Coverage, based on selected sessions at the:  21st Annual Scientific Meeting of the American Pain Society
Disclosures – Presented by:  Serge Marchand, PhD (Moderator), Kathleen Sluka, PT, PhD, Daniel Le Bars, PhD  Pierre Rainville, PhD

Summarized by: Zahid H. Bajwa, MD, and Charles Ho, MD, Serge Marchand, PhD,[1] from the University of Quebec, Canada, moderated the symposium "Endogenous Pain Modulation Systems: From Fundamental Research to Clinical Application." The panel discussed 3 levels of endogenous pain modulation mechanisms: Superior central control involves the cognitive factors that modulate the perception of pain; descending mechanisms produce a diffuse analgesia; spinal controls, as postulated by the gate control theory, involve peripheral stimuli that produce local analgesia.

Spatial Summation and Endogenous Pain Inhibition

Dr. Marchand presented his findings about the spatial summation effect,[2] which is the relationship between the size of the surface stimulated and perceived pain intensity. Marchand described a study in which subjects were immersed in nociceptive hot water along segments of the surface of their arms, between the fingertips and shoulders.

Investigators used three types of immersion sessions: immersion beginning at the fingertips and increasing to the shoulders (increasing session); immersion beginning at the shoulders and decreasing to the fingertips (decreasing session); immersion of the entire arm followed by an increasing session, from fingertips to shoulders. They found that pain perception correlated with the size of the surface stimulated during decreasing sessions and whole-arm immersions plus increasing sessions (a positive spatial summation effect). No spatial summation effect was found during the increasing sessions alone.

Marchand hypothesized that the increasing sessions produced no spatial summation effect because inhibitory mechanisms are gradually recruited at the same time as excitatory mechanisms, thus neutralizing spatial summation.

In the decreasing sessions and the whole-arm immersion plus increasing sessions, a spatial summation effect was produced because the inhibitory mechanisms were fully recruited at the beginning of the sessions when largest surface areas were immersed. This allows a positive relationship between the size of the surface area stimulated and pain perception.

The fact that patients suffering from fibromyalgia presented a positive relation between the surface stimulated and pain perception during both decreasing and increasing sessions, supports the suggestions that fibromyalgic pain could be the result of a deficit of endogenous pain inhibitory systems. These results could lead to a better understanding of the mechanisms and treatment of fibromyalgia.

Transcutaneous Electrical Nerve Stimulation

The next speaker, Kathleen Sluka, PT, PhD,[1] from the University of Iowa Physical Therapy and Rehabilitation Science Graduate Program, discussed the neurobiology of transcutaneous electrical nerve stimulation (TENS). TENS is the application of electrical stimulation to the skin for pain control. Despite extensive use of TENS for relieving pain, the underlying mechanisms remain unclear.

TENS includes 3 parameters: frequency, intensity, and pulse duration. Low frequencies are those less than 10 Hz and produce motor stimulation. High frequencies are greater than 50 Hz and produce sensory stimulation. Pulse duration ranges from 10-250 mcsec. TENS reduces noxious evoked responses and spontaneous firing of dorsal horn neurons.

The actions of high-frequency TENS are typically explained by the gate-control theory, in which stimulation of large-diameter afferents attenuates nociceptive fiber-evoked responses in the dorsal horn of the spinal cord. The effectiveness of low-frequency TENS is believed to be mediated by the release of endogenous opioids. Sluka noted that both high- and low-frequency TENS are mediated by activation of opioid receptors in the spinal cord and in the rostral ventromedial medulla. Specifically, naloxone, a mu-opioid antagonist, blocks the analgesia produced by low-frequency TENS,[3] whereas in high-frequency TENS, high doses of naloxone reverses analgesia. However, naltrindole, a delta-opioid antagonist, blocks the analgesia produced by high-frequency TENS.[3]

High-frequency TENS increases cerebral spinal fluid concentrations of beta-endorphins, met-enkephalin, and deltorphin. Depletion of 5-HT, a neurotransmitter of the descending inhibitory pathway, attenuates the antinociceptive effect of high-frequency TENS. This suggests that descending inhibitory pathways play a role in TENS analgesia.

In the inflammatory animal models of pain, high-frequency TENS caused partial reduction of primary hyperalgesia, whereas low-frequency TENS did not.[4,5] Both high- and low-frequency TENS caused complete reductions in secondary hyperalgesia. Spinal blockade of mu-opioid receptors prevented low-frequency antihyperalgesia, and spinal blockade of delta-opioid receptors prevented high-frequency antihyperalgesia.

If TENS works through opioids, will it work with morphine-tolerant animals, and can TENS cause tolerance? Sluka and colleagues[4] found low-frequency, but not high-frequency, TENS to be less effective in morphine-tolerant rats. Repeated applications of TENS also produced tolerance.

Dr. Sluka concluded that low-frequency TENS should not be used if the patient is tolerant to morphine, but high-frequency TENS may still be effective. Because repeated use of TENS can lead to tolerance, the optimal timing should be found between treatments to promote efficacy while preventing tolerance. TENS may be more effective for secondary hyperalgesia and referred pain than for primary hyperalgesia, and high-frequency TENS may be more effective than low-frequency TENS.

Diffuse Noxious Inhibitory Controls

Daniel Le Bars, PhD, from INSERM, Paris, France, discussed an intriguing hypothesis in his presentation, "Diffuse Noxious Inhibitory Controls (DNIC): Are They Sculptors of the Body Schema?"[1] In animal studies, Le Bars and associates[6-8] have shown that pain occurring in one part of the body reduces pain in the rest of the body by activating DNIC, which are supraspinal structures that modulate the transmission of nociceptive signals.

Wide dynamic range (WDR) neurons include dorsal horn interneurons. Segmental cutaneous fields can be excitatory or inhibitory, and capture all information coming from the skin (external milieu) and viscera (internal milieu).

A "whole-body receptive field" is activated when the rest of the body is the source of inhibition. In a rat model, one can inhibit pain by stimulating any part of the animal. Thus, the WDR may constitute a rearrangement of the body schema which is perturbed by pain.

Pain Related Cerebral Activity

Pierre Rainville, PhD, of the Department of Stomatology, Faculty of Dentistry at the University of Montreal, Quebec, Canada, concluded the symposium with a review of studies on pain-related cerebral activity in humans.[1, 9-11] Pain stimuli exert activity in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), anterior cingulate cortex (ACC), insular cortex, and thalamus. The process is a parallel and serial nociceptive experience. Hypnosis can modulate the nociceptive process when the central control mechanisms (motivational-affective system) influence the sensory-discriminative system. Hypnosis has been shown to affect spinal modulation.

Hypnotic analgesia reduces the late somatosensory-evoked potentials and affects the R-III reflex, the spinal nociceptive flexion reflex.

Hypnosis can cause a cognitive modulation of pain. It can reduce the perception of unpleasantness even though the patient registers the same physiologic intensity of pain. In a recent study, Rainville and colleagues[9] found that activity in the dorsal ACC and prefrontal cortex increases during hypnotic suggestion for pain modulation. Hypnotic modulation of the intensity of pain can change the activity of S1.

This group also found that pain can be modulated by attention. When patients listened to musical tones, there was reduced pain-related S1 activity. Likewise, pain can be modulated by emotions, with an overlap between pain- and emotion-related areas. Finally, pain was attenuated with endogenous activation of the mu-opioid system in key areas.

The mechanisms of pain modulation are still being elucidated. The gate-control theory was a giant leap in concept but very simplistic in mechanism. The roles of spatial summation, interneurons, opioids, and brain areas are slowly being defined by their effects of pain modulation, and may be part of Dr. Melzack's "neuromatrix" theory.


1. Marchand S, Sluka K, Le Bars D, Rainville P. Symposium: Endogenous Pain Modulation Systems: From Fundamental Research to Clinical Application. Program and Abstracts of the 21st Annual Scientific Meeting of the American Pain Society; March 14-17, 2002; Baltimore, Maryland. Abstract 310.

2. Marchand S, Arsenault P. Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms. Pain. 2002;95:201-206.

3. Kalra A, Urban MO, Sluka KA. Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther. 2001;298:257-263.

4. Sluka KA, Judge MA, McColley MM, et al. Low frequency TENS is less effective than high frequency TENS at reducing inflammation-induced hyperalgesia in morphine-tolerant rats. Eur J Pain. 2000;4:185-193.

5. Sluka KA, Deacon M, Stibal A, et al. Spinal Blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats. J Pharmacol Exp Ther. 1999;289:840-846.

6. Danziger N, Gautron M, LeBars D, et al. Activation of diffuse noxious inhibitory controls (DNIC) in rats with an experimental peripheral mononeuropathy. Pain. 2001;91:287-296.

7. Danziger N, Weil-Fugazza J, Le Bars D, et al. Alteration of descending modulation of nociception during the course of monoarthritis in the rat. J Neurosci. 1999;19:2394-2400.

8. Le Bars D, Villanueva L, Bouhassira D, et al. Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter. 1992;4:55-65.

9. Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical representation of the sensory dimension of pain. J Neurophysiol. 2001;86:402-411.

10. Rainville P, Carrier B, Hofbauer RK, et al. Dissociation of sensory and affective dimensions of pain using hypnotic modulation. Pain. 1999;82:159-171.

11. Rainville P, Hofbauer RK, Paus T, et al. Cerebral mechanisms of hypnotic induction and suggestion. J Cogn Neurosci. 1999;11:110-125.

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2 thoughts on “Endogenous Factors That Modulate Pain: Implications for Treating Fibromyalgia”

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