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Substance P in CSF of patients with chronic pain syndromes ... genic) pain tended to have higher endorphin levels which were ..... psychogenic pain syndromes.
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Pain, 33 (1988) 3-9 Elsevier PAI 01199

Clinical Section Substance P in CSF of patients with chronic pain syndromes B.G.L. Almay *, F. Johansson *, L. Von Knorring * *, P. Le GrevCs * * * and L. Terenius * * * *Department of Neurology, UmeH University, S-901 85 .!Jme&(Sweden), * * Department of Psychiatry, Urned”Uniuersity, S-901 85 Umd

(Sweden), and * * * Department

of Pharmacology,

Uppsala University, S- 151 24 Uppsala (Sweden)

(Received 2 June 1987, revision received 25 November 1987, accepted 2 December 1987)

Immunoreactive substance P was determined in lumbar CSF of 35 healthy volunteers and 60 patients with chronic pain syndromes of at least 6 months duration. No significant relationships were found between substance P levels and age, sex or body height. Substance P levels were lower in chronic pain patients, with either neurogenic (n = 23) or idiopathic pain (n = 37) syndromes, than in the healthy volunteers. Substance P levels were especially low in patients with neurogenic pain with lesions involving the extremities and in those with polyneuropathy, while patients with central pain or pain of the head or face had higher values. Substance P levels were related to depressive symptomatology as determined by means of visual analogue scales and to stable personality traits as determined by means of the Karolinska Scales of Personality (KSP). The most consistent (and inverse) relationship was found between substance P levels and the symptom ‘inner tension’ and between substance P levels and the personality trait ‘psychic anxiety.’ Summary

Key

words:

Substance P, CSF; Depressive s~ptomatology;

Personality traits; Chronic pain

Introduction The neuropeptide substance P is found in several major neuronal pathways. Several of these have been associated with pain. For instance, about 80% of substance P containing nerve terminals in the spinal cord are from small-diameter primary afferent fibers terminating in the most dorsal part of the dorsal horn. These fibers transmit painful stimuli, and substance P has been proposed as a pain stimulus transmitter in primary afferents [17,18]. The substance P nerve terminals are topologically associated with enkephahn terminals, in dorsal spinal cord as well as in brain-stem and higher CNS centers known to be involved in pain transmission and modulation [e.g., 121. The spinal cord also receives innervation from the raphe sys-

Correspondence to: Lam Von Knorring, M.D., Department of Psychiatry, Ume% University, S-901 85 Urn&, Sweden.

tern with fibers having substance P or substance P and serotonin [10,13]. There are also major CNS pathways with substance P which are not directly involved in the experience of pain including a striato-nigral pathway [e.g., 8,111. Furthermore, the innervation of the cerebral cortex of the human brain is particularly rich in substance P [18]. We have previously measured various neurochemical markers in the cerebrospinal fluid of patients with chronic pain. These studies have demonstrated a discrimination of patients with respect to certain clinical criteria. Patients with chronic pain of neurogenic origin frequently had low endo~~n 12,231 and serotonin metabolite levels [4], as compared with healthy volunteers. Patients with idiopathic (formerly termed psychogenic) pain tended to have higher endorphin levels which were inversely related to the severity of depression. Preliminary results also indicated that CSF levels of substance P were tow in patients

0304-3959/88/$03.50 0 1988 Elsevier Science Publishers B.V. (Biomedical Division)

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with chronic neurogenic pain and rose with repeated treatment with transcutaneous nerve stimulation [25]. The present study gives data from a larger patient sample characterized by various clinical parameters and certain stable personality traits.

Materials and methods Subjects

The series included 60 patients with chronic pain syndromes, of at least 6 months duration, hospitalized at the Department of Neurology, UmeA University. Patients with a history of alcohol or drug abuse or with psycho-organic cerebral syndromes were excluded. None of the patients had previously been taking narcotic analgesics. At the time of admission most drugs were stopped. Thus, at examination most patients were drug-free. The localization of pain, the suspected etiology of the pain syndromes and earlier drug treatment are described in more detail by Almay [l]. There were 23 patients, 14 male and 9 female, with a mean age of 54.2 & 15.3 years, who had clearly defined neurogenic pain syndromes according to the following definition: spontaneous pain associated with a primary lesion or a disturbance of the function of the central or peripheral nervous system, produced by external or internal causes. The pain is often associated with various patterns of qualitative and quantitative sensory abnormalities and is sometimes also combined with motor paresis of central or peripheral origin. The pain can arise in any part of the neural system and is usually confined to nerve segments and dermatomes but, especially in long-standing cases, diffuse irradiating pain can be found. The mean duration of the pain syndromes was 104 k- 135 months. The series is described in more detail by Almay [l]. There were 37 patients, 25 male and 12 female, with a mean age of 45.0 f 8.6 years, who had idiopathic pain syndromes according to the definition given by Williams and Spitzer [27]: (1) Preoccupation with severe pain of at least 6 months duration is a predominant disturbance. (2) The pain presented as a symptom is incon-

sistent with the anatomic distribution of the nervous system; after extensive evaluation no organic pathology or pathophysiological rnechanism can be found to account for the pain; or when there is some related organic pathology, the complaint is grossly in excess of what would be expected from the physical findings. (3) Pain is not due to somatization disorder or major depression. According to the definition, this group comprises both patients in whom no somatic lesion is found and patients in whom neurogenic or nociceptive lesions are found but in whom the complaint is regarded as grossly in excess of what would be expected from the psysical findings. In the present series, 10 patients with idiopathic pain syndromes did not present any somatic lesions while 14 had nociceptive lesions, 4 had neurogenic lesions and 9 had combined nociceptive and neurogenic lesions. This classification was based on general clinical investigation supported by roentgenologic, electrophysiologic and biopsy findings. The mean duration of the pain syndromes was 64.9 -t 69.1 months. The series is described in more detail by Almay [l]. The chronic pain patients were compared to 35 healthy volunteers, 16 males and 19 females, with a mean age of 29.9 t- 5.2 years. The healthy volunteers were mostly people working at the Departments of Psychiatry and Neurology at Umes University or their relatives. They followed the same experimental procedures as the chronic pain patients. Several comparisons between the investigated groups were tested statistically to avoid a selection bias. Although there was a majority of females in the group of healthy volunteers, there was no statistically significant sex difference between the 3 groups (x2 = 3.63, df 2, n.s.). However, there was a significant age difference between the groups, with the youngest subjects among the healthy volunteers and the oldest among the patients with neurogenic pain syndromes (F = 47.06, P < 0.001). Patients with neurogenic pain syndromes had a somewhat longer duration of their pain syndromes than the patients with idiopathic pain syndromes; the difference between the groups was, however, not significant (t = 1.48, n.s.).

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Since there is a possibility of a substance P gradient within the CSF compartment, the body heights in the different groups could be of importance. However, no significant differences were found between healthy volunteers, 171.9 + 9.6 cm, patients with neurogenic pain syndromes, 170.9 f 9.1 cm and patients with idiopathic pain syndromes, 172.9 + 7.7 cm (F= 0.39 ns.). Clinical evaluation Seventy-one subjects completed a series of visual analog scales (VAS) covering pain, sadness, inner tension, bodily discomfort, concentration difficulties and memory disturbances. All 6 scales consisted of a 100 mm long horizontal line with definitions at the end points and no marks in between. The scales have been used earlier and the validity and the reliability have been found to be quite satisfactory [15]. The personality inventory used has been constructed for research purposes at the Departments of Psychiatry and Psychology of the Karolinska Institute in Stockholm to measure stable personality traits [20]. The inventory is called KSP (Karolinska Scales of Personality). The inventory comprises 135 questions grouped in 15 scales: Psychic anxiety, Somatic anxiety, Muscular tension, Social desirability, Impulsiveness, Monotony avoidance, Detachment, Psychasthenia, Socialization, Indirect aggression, Verbal aggression, Irritability, Suspicion, Guilt and Inhibition of aggression. Furthermore, 3 scales with items loading high in the Buss aggression factor (Indirect aggression, Verbal aggression and Irritability) and 2 scales with items loading high in the Buss Hostility factor (Guilt and Suspicion) have been combined into 2 composite factor scales of Aggression and Hostility. The inventory has been described in detail by Von Knorring et al. [24] and has been applied to patients with chronic pain syndromes by Carlsson [9] and Von Knorring et al. [26]. Seventy-six subjects completed the KSP. Radioimmunoassay (RIA) A sample of 12.5 ml CSF was obtained by lumbar puncture in the morning after 12 h of rest with the subjects in a lateral recumbent position. The fluid was carefully mixed, then immediately centrifuged, divided into 3 ml portions and stored

frozen at - 80 ’ C for later analysis of substance P. Determination of substance P-like immunoreactivity was performed according to the method described by Tamsen et al. [22]. Briefly, CSF samples (2-3 ml) were run through Sep Pat disposable reverse phase silica gel columns (Waters, Milford, MA). The columns were washed with 10 ml distilled water and then eluted with 3 ml methanol0.1% trifluoroacetic acid. The eluates were evaporated in vacua and the samples were redissolved in 100 ~1 methanol-O.1 M HCl(1 : 1, v/v)_ Twenty-five ~1 of the sample were introduced into the RIA with antiserum (final dilution 1 : 100,000) and 12’I-labeled Tyr ‘-substance P tracer (approx. 5000 counts/mm). The final volume was 225 ~1. Samples were incubated overnight at 4°C and incubation was terminated by the addition of activated charcoal. The sensitivity of the assay was 2.5 fmol substance P/tube. Cross-reactivity of the antiserum for substance P (3-11) and (4-11) was loo%, with substance P (5-11) 60% and with (6-11) 20%. There was no (< 0.01%) cross-reaction with substance P (l-7), substance P free acid, substance P-Gly12, enkephalins or /3-endorphin. Statistics Differences in frequency distributions were tested by means of the x2 test. With less than 5 subjects expected in one cell, Yates’ correction was made. Differences between means of 2 groups were tested by means of Student’s t test and for more than 3 groups by means of analysis of variance, one-way classification (ANOVA). Correlations were sought by means of the Spearman rank correlation coefficient. All computations were made at the Umel Computer Center (UMDAC) by means of the Statistical Package for the Social Sciences (SPSS).

Results

Within the series of healthy volunteers, there was no significant difference in substance P levels with regard to sex (males 9.4 + 3.6, females 9.9 f 2.9, t = 0.49, n.s.), nor any significant correlation

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IABl,l.

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IMMUNOREACTIVE SUBSTANCE. P IN C‘SF OF HEALTHY VOLUNTEERS (N = 35) AND P4TlENTS WITH CHRONIC PAIN SYNDROMES (N = 60, Mean f S.D.. ANOVA.

[MMCJNOREACT‘IVE StiBSTANC‘k I’ IN (‘Sk OF 7lENTS WITH CHRONIC NEUROGENIC PAIN, VIDED INTO SUBGROL!PS 4