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Do low levels of Beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.ORCID iD: 0000-0003-4420-418X
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Pain and Rehabilitation Centre.
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
2014 (English)In: Pain medicine (Malden, Mass.), ISSN 1526-2375, E-ISSN 1526-4637, Vol. 15, no 1, 111-119 p.Article in journal (Refereed) Published
Abstract [en]

Objective

Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF).

Design

Cross-sectional, comparative, observational study.

Subjects

Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included.

Methods

Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit.

Results

We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs rs = 0.574, P = 0.032).

Conclusions

Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014. Vol. 15, no 1, 111-119 p.
Keyword [en]
Beta-Endorphin; Biomarker; Cerebrospinal Fluid; Neuropathic; Pain; Substance P
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-104231DOI: 10.1111/pme.12248ISI: 000329756400011OAI: oai:DiVA.org:liu-104231DiVA: diva2:695697
Available from: 2014-02-12 Created: 2014-02-12 Last updated: 2017-12-06Bibliographically approved
In thesis
1. The Cerebrospinal Fluid in Severe Pain Conditions: Clinical, Pharmacological and Proteomic Aspects
Open this publication in new window or tab >>The Cerebrospinal Fluid in Severe Pain Conditions: Clinical, Pharmacological and Proteomic Aspects
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain.

In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question.

In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor.

In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 94 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1465
National Category
Anesthesiology and Intensive Care Neurosciences
Identifiers
urn:nbn:se:liu:diva-121494 (URN)10.3384/diss.diva-121494 (DOI)978-91-7519-032-7 (ISBN)
Public defence
2015-11-13, Berzeliussalen, Ingång 65, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-09-22 Created: 2015-09-22 Last updated: 2015-09-23Bibliographically approved

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