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The Cerebrospinal Fluid in Severe Pain Conditions: Clinical, Pharmacological and Proteomic Aspects
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.ORCID iD: 0000-0003-4420-418X
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: urn:nbn:se:liu:diva-121494DOI: 10.3384/diss.diva-121494ISBN: 978-91-7519-032-7 (print)OAI: oai:DiVA.org:liu-121494DiVA: diva2:855867
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
List of papers
1. Movement-evoked breakthrough cancer pain despite intrathecal analgesia: a prospective series
Open this publication in new window or tab >>Movement-evoked breakthrough cancer pain despite intrathecal analgesia: a prospective series
2011 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 55, no 9, 1139-1146 p.Article in journal (Refereed) Published
Abstract [en]

Background: Intrathecal analgesia (ITA) is a valuable treatment option for intractable cancer-related pain. However, the issue of movement-evoked breakthrough pain (BTP) has not been specifically investigated in the ITA setting. The aim of the study was to evaluate the effect of ITA on spontaneous resting pain intensity (SRPI), doses of non-ITA opioids, and specifically on movement-evoked pain intensity (MEPI). less thanbrgreater than less thanbrgreater thanMethods: We prospectively studied 28 consecutive patients who graded SRPI and MEPI on a 0-10 numerical rating scale (NRS) at the time of ITA procedure, after 1 week, and after 1 month. Mild pain was defined as NRS andlt;= 3 and severe pain as NRS andgt;= 7. Concomitant doses of opioids were registered. less thanbrgreater than less thanbrgreater thanResults: After 1 week, no patient had severe SRPI compared with 31% before ITA, and the proportion of patients with mild SRPI had increased from 27% to 76%. Meanwhile, the median daily dose of non-ITA opioids decreased from 575 to 120 mg of oral morphine equivalents. The effect on SRPI and on doses of non-ITA opioids remained essentially unchanged during the study month, but the proportion of patients having severe MEPI did not change significantly: 44% still had severe MEPI after 1 week and 40% after 1 month. less thanbrgreater than less thanbrgreater thanConclusion: Movement-evoked BTP was a major clinical problem throughout the study month despite otherwise successful ITA. Improving the quality of life of patients with intractable cancer-related pain should include developing strategies to better deal with movement-evoked BTP.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71376 (URN)10.1111/j.1399-6576.2011.02510.x (DOI)000295102500015 ()
Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2017-12-08
2. Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment
Open this publication in new window or tab >>Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment
2015 (English)In: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 18, no 5, 404-413 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. Material and Methods: Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5g, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. Results: We found a low proportion of responders (13%). However 30% of patients experienced greater than= 30% pain reduction on a least one injection, yielding a number needed to treat of similar to 3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6h) (p = 0.047) after a mean ziconotide dose of 2.75 mu g. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. Conclusions: Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

Place, publisher, year, edition, pages
Wiley, 2015
Keyword
Bolus; intrathecal; spinal; trialing; ziconotide
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-120352 (URN)10.1111/ner.12293 (DOI)000357388400010 ()25879804 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland; Swedish Research Council

Available from: 2015-07-31 Created: 2015-07-31 Last updated: 2017-12-04
3. 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
Open this publication in new window or tab >>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
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
Keyword
Beta-Endorphin; Biomarker; Cerebrospinal Fluid; Neuropathic; Pain; Substance P
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-104231 (URN)10.1111/pme.12248 (DOI)000329756400011 ()
Available from: 2014-02-12 Created: 2014-02-12 Last updated: 2017-12-06Bibliographically approved
4. Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls: a hypothesis-generating pilot study
Open this publication in new window or tab >>Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls: a hypothesis-generating pilot study
Show others...
2015 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 8, 321-333 p.Article in journal (Refereed) Published
Abstract [en]

Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

Place, publisher, year, edition, pages
Dovepress, 2015
Keyword
Cerebrospinal fluid, multivariate data analysis, neuropathic pain, proteomics
National Category
Nursing Surgery
Identifiers
urn:nbn:se:liu:diva-121493 (URN)10.2147/JPR.S82970 (DOI)000364718500002 ()26170714 (PubMedID)
Note

Funding agencies: Swedish Research Council; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland (Sinnescentrum); Halsofonden foundation

Available from: 2015-09-22 Created: 2015-09-22 Last updated: 2017-12-05Bibliographically approved

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