uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy. (Division of Biological Research on Drug Dependence)
Precision System Science Japan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
Show others and affiliations
2013 (English)In: Molecular Brain, ISSN 1756-6606, Vol. 6, 8- p.Article in journal (Refereed) Published
Abstract [en]

Background

Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.

Results

The plasma β-endorphin levels were significantly higher in controls than in pain patients.

A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.

Conclusions

Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids.

Place, publisher, year, edition, pages
2013. Vol. 6, 8- p.
Keyword [en]
chronic pain, opioid sensitivity, beta-endorphin, mu-1-opioid receptor (OPRM1), calcium channel subunit 2 (CACNA2D2), ATP-binding cassette B1 (ABCB1)
National Category
Anesthesiology and Intensive Care Medical and Health Sciences Neurosciences
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:uu:diva-129623DOI: 10.1186/1756-6606-6-8ISI: 000316319900001PubMedID: 23402298OAI: oai:DiVA.org:uu-129623DiVA: diva2:344564
Available from: 2010-08-19 Created: 2010-08-19 Last updated: 2017-12-12
In thesis
1. Long-term Effects of Opioids in the Treatment of Chronic Pain: Investigation of Problems and Hazards on Clinical, Biochemical, Cellular and Genetic Levels
Open this publication in new window or tab >>Long-term Effects of Opioids in the Treatment of Chronic Pain: Investigation of Problems and Hazards on Clinical, Biochemical, Cellular and Genetic Levels
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

After two decades of liberal prescribing of opioids, there has been an increasing recognition of problems connected to the prolonged use of opioids for chronic pain.

The aim of my thesis was to explore some consequences of long-term opioid treatment for chronic pain such as problematic opioid use, endocrine disorders, tolerance and genetic variations in pain and opioid response.

Sixty patients with severe pain and problematic opioid use were treated with a structured methadone programme. Risk factors were musculoskeletal pain, psychiatric co-morbidity and previous addiction. Treatment resulted in good pain relief and improved quality of life, but function was impaired by side effects indicating endocrine dysregulation.

The possibility of opioid-induced endocrine dysfunction was explored in the second paper, where 40 pain patients treated with strong opioids and 20 pain patients without treatment of strong opioids were investigated. The opioid-treated patients had significantly higher incidence of endocrine disturbance affecting gonadal and adrenal function and prolactin levels.

The functionality of the μ-receptor after long-term treatment with morphine, saline and naloxone was explored in a cell-line expressing the μ-receptor. After one and four weeks of treatment the binding was tested with morphine, methadone, fentanyl and DAMGO and function measured by GTP γ-assay. The binding of DAMGO was significantly diminished after 4 weeks in cells treated with morphine compared with saline and naloxone.

Genetic variation in three genes with functional impact on opioid response and pain sensitivity was investigated in 80 patients with chronic low-back pain and differential opioid sensitivity and in 56 healthy controls. The results indicated a higher incidence of opioid-related side effects and gender differences in patients with the minor allele of the ABCB1 gene, a correlation between increased opioid sensitivity and the major CACNA2D2 allele and a possible relationship between intrinsic protection against chronic pain and the minor allele of OPRM1.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 586
Keyword
opioid, chonic pain, long-term opioid treatment
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:uu:diva-129624 (URN)978-91-554-7866-7 (ISBN)
Public defence
2010-09-25, Auditorium minus, Gustavianum, Akademigatan 3, 753 10 Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-09-02 Created: 2010-08-19 Last updated: 2011-01-14Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Rhodin, AnnicaGröndbladh, AlfhildNIlsson, Kent WRosenblad, AndreasZhou, QinEnlund, MatsHallberg, MathiasGordh, TorstenNyberg, Fred

Search in DiVA

By author/editor
Rhodin, AnnicaGröndbladh, AlfhildNIlsson, Kent WRosenblad, AndreasZhou, QinEnlund, MatsHallberg, MathiasGordh, TorstenNyberg, Fred
By organisation
Anaesthesiology and Intensive CareCentre for Clinical Research, County of VästmanlandDisciplinary Domain of Medicine and PharmacyDepartment of Pharmaceutical Biosciences
In the same journal
Molecular Brain
Anesthesiology and Intensive CareMedical and Health SciencesNeurosciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 608 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf