| 1. |
- Heddini, Ulrika, et al.
(författare)
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A118G polymorphism in the μ-opioid receptor gene and levels of β-endorphin are associated with provoked vestibulodynia and pressure pain sensitivity
- 2014
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Ingår i: Scandinavian Journal of Pain. - : Elsevier. - 1877-8860 .- 1877-8879. ; 5:1, s. 10-16
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Tidskriftsartikel (refereegranskat)abstract
- Background and aimsProvoked vestibulodynia (PVD) is the most common cause of dyspareunia among young women. The aetiology is largely unknown and treatment is often extensive and longstanding with varying outcomes. Patients display general pain hypersensitivity and there are correlations with other chronic pain syndromes such as fibromyalgia later in life. The A118G polymorphism in the μ-opioid receptor (OPRM1) gene influences endogenous pain regulation and pain sensitivity, but has not been studied in this patient group before. We aimed to investigate a possible association between A118G polymorphism and PVD, with correlation to plasma levels of β-endorphin, and to explore relationships between this polymorphism and pain sensitivity among women with PVD and healthy controls.MethodsThis case–control study included 98 women with PVD and 103 controls. Participants filled out study-specific questionnaires and underwent quantitative sensory testing of pressure pain thresholds on the arm, leg and in the vestibular area. Levels of β-endorphin were analyzed by radioimmunoassay using the EURIA-beta-endorphin kit, and the A118G single-nucleotide polymorphism (SNP; rs1799971) in the OPRM1 gene was analyzed using the TaqMan SNP genotyping assay.ResultsThe 118G allele was more common in controls (44%) than in patients (30%) (p = 0.042). The odds ratio of having PVD was 1.8 in participants carrying the 118A allele compared to participants hetero- or homozygous for the 118G allele (OR = 1.846, CI: 1.03–3.31, p = 0.039). Pressure pain thresholds on the leg were higher for participants carrying the 118G allele (mean 480 kPa, SD 167.5) than for those carrying the 118A allele (mean 419, SD 150.4, p = 0.008). Levels of β-endorphin were higher in patients (mean 17.9 fmol/ml, SD 4.71) than in controls (mean 15.8 fmol/ml, SD 4.03) (p < 0.001).ConclusionWe found an association between the A118G polymorphism in the OPRM1 gene and an increased risk of PVD and increased pain sensitivity among participants carrying the 118A allele. PVD patients were more sensitive to pressure pain and had higher levels of plasma β-endorphin than controls. The results indicate that differences in endogenous pain modulation involving the opioid system could contribute to the pathophysiology of PVD and the general pain hypersensitivity seen in these women.ImplicationsThe data support the conceptualization of PVD as part of a general pain disorder with a possible genetic predisposition. The age of onset of PVD is usually between 18 and 25 years and already at this age general pain hypersensitivity is present but rarely causing disability. We believe that early recognition and treatment, with the risk of further development of chronic pain taken into consideration, might prevent future aggravated pain problems in this patient group.
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| 2. |
- Heddini, Ulrika, et al.
(författare)
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GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia
- 2012
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 8, s. 68-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Provoked vestibulodynia (PVD) is a pain disorder localized in the vestibular mucosa. It is the most common cause of dyspareunia among young women and it is associated with general pain hypersensitivity and other chronic pain conditions. Polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene has been found to influence general pain sensitivity and the risk of developing a longstanding pain condition. The aim of this study was to investigate GCH1-polymorphism in women with PVD and healthy controls, in correlation to pain sensitivity. Results: We found no correlation between the previously defined pain-protective GCH1-SNP combination and the diagnosis of PVD. Nor any correlation with pain sensitivity measured as pressure pain thresholds on the arm, leg and in the vestibule, coital pain scored on a visual analog scale and prevalence of other bodily pain conditions among women with PVD (n = 98) and healthy controls (n = 102). However, among patients with current treatment (n = 36), there was a significant interaction effect of GCH1-gene polymorphism and hormonal contraceptive (HC) therapy on coital pain (p = 0.04) as well as on pressure pain thresholds on the arm (p = 0.04). PVD patients carrying the specified SNP combination and using HCs had higher pain sensitivity compared to non-carriers. In non-HC-users, carriers had lower pain sensitivity. Conclusions: The results of this study gave no support to the hypothesis that polymorphism in the GCH1-gene contributes to the etiology of PVD. However, among patients currently receiving treatment an interaction effect of the defined SNP combination and use of hormonal contraceptives on pain sensitivity was found. This finding offers a possible explanation to the clinically known fact that some PVD patients improve after cessation of hormonal contraceptives, indicating that PVD patients carrying the defined SNP combination of GCH1 would benefit from this intervention.
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| 3. |
- Heddini, Ulrika, et al.
(författare)
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Provoked Vestibulodynia-Medical Factors and Comorbidity Associated with Treatment Outcome
- 2012
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Ingår i: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095 .- 1743-6109. ; 9:5, s. 1400-1406
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Provoked vestibulodynia (PVD) is the most common cause of dyspareunia in young women. The etiology is unclear, and there is little knowledge of how to predict treatment outcome. Aim. The aim of this study was to identify medical factors associated with treatment outcome and coital pain in women with PVD. Methods. Seventy women previously treated for PVD at a vulvar open care unit completed questionnaires and a quantitative sensory testing session. Main Outcome Measures. Concomitant bodily pain and treatment outcome were surveyed using a study specific questionnaire. Coital pain was rated on a visual analog scale (VAS), range 0100. Psychometric screening was carried out using the Hospital Anxiety and Depression Scale. Pressure pain thresholds on the arm, leg, and in the vestibulum were measured using pressure algometers. Results. Major improvement/complete recovery was more likely in PVD patients with a maximum of one other concomitant pain disorder compared with patients with four or more (odds ratio = 7.8, confidence interval: 1.249.4, P = 0.03). In a multiple linear regression model, the number of other pain disorders (P < 0.01) and a diagnosis of primary PVD (P = 0.04) were positively associated with the coital VAS pain score. Women with secondary PVD reported major improvement/complete recovery to a higher extent than women with primary PVD (z = 2.11, P = 0.04). Conclusion. A successful treatment outcome was more likely in PVD patients with fewer other concomitant pain conditions. The number of other bodily pain conditions was also associated to the intensity of the coital pain. Additionally, the results indicate higher incomplete response rates to treatment in women with primary PVD compared with secondary PVD.
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| 4. |
- Heddini, Ulrika, et al.
(författare)
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Serotonin Receptor Gene (5HT-2A) Polymorphism is Associated with Provoked Vestibulodynia and Comorbid Symptoms of Pain
- 2014
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Ingår i: Journal of Sexual Medicine. - : ELSEVIER SCI LTD. - 1743-6095 .- 1743-6109. ; 11:12, s. 3064-3071
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionProvoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AimWe aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. MethodsIn this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. Main Outcome MeasuresConcomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. ResultsThe probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. ConclusionThe results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders. Heddini U, Bohm-Starke N, Gronbladh A, Nyberg F, Nilsson KW, and Johannesson U. Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain. J Sex Med 2014;11:3064-3071.
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| 5. |
- Haraldson, Philip, et al.
(författare)
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Botulinum Toxin A as a Treatment for Provoked Vestibulodynia A Randomized Controlled Trial
- 2020
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Ingår i: Obstetrics and Gynecology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0029-7844 .- 1873-233X. ; 136:3, s. 524-532
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate pain reduction after two injections of 50 units botulinum toxin A compared with placebo for provoked vestibulodynia. METHODS: We conducted a double-blinded, placebo-controlled randomized trial of 50 units botulinum toxin A or placebo injected in the bulbocavernosus muscles twice, 3 months apart, in women with provoked vestibulodynia. Primary outcome was self-reported dyspareunia or pain at tampon use on a visual analog scale (VAS, 0-100). Secondary outcomes were pain at weekly tampon insertion (VAS score), reduction of pelvic floor hypertonicity (measured with a vaginal manometer), adverse events, and sexual function and distress. A sample size of 38 participants for each group was calculated to achieve a statistical power of 80% based on an effect size of 20 VAS units (0-100) (mean score range 56-76 +/- 31 SD). RESULTS: Between May 2016 and June 2018, 124 women with provoked vestibulodynia were assessed, and 88 were randomized to botulinum toxin A (BTA group, n=44) or placebo (placebo group, n=44). Primary outcome showed a lower but statistically nonsignificant pain rating by 7 VAS units (95% CI -15.0 to 0.4) in the BTA group compared with the placebo group. Secondary results showed a significant decrease in pain at weekly tampon insertion by 11 VAS units (95% CI -16.6 to 6.0) with botulinum toxin A injection. The vaginal manometer measured lower maximum contraction strength by 7 mm Hg (95% CI -12.7 to -2.4) and lower 10-second endurance strength by 4 mm Hg (95% CI -7.72 to -1.16) in the BTA group compared with the placebo group. No changes were observed for sexual function and distress, but there was a significant increase in women attempting vaginal intercourse in the BTA group (0.27, 95% CI 0.06-0.48). No severe adverse events were reported. CONCLUSION: Twice-repeated injections of 50 units of botulinum toxin A in women with provoked vestibulodynia did not reduce dyspareunia or pain at tampon use, but secondary outcomes suggested positive effects of the treatment.
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| 6. |
- Haraldson, Philip, et al.
(författare)
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Botulinum Toxin A for Provoked Vestibulodynia : 12 Months’ Follow-up of a Randomized Controlled Trial
- 2022
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Ingår i: Journal of Sexual Medicine. - : Elsevier B.V.. - 1743-6095 .- 1743-6109. ; 19:11, s. 1670-1679
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Tidskriftsartikel (refereegranskat)abstract
- Background: Provoked vestibulodynia (PVD) is a common pain disorder afflicting primarily young women, and botulinum toxin A (BTA) has been to a limited extent tested as a treatment. Aim: Evaluate outcome 12 months after injection with BTA as a treatment for PVD. Methods: We conducted a double-blinded, placebo-controlled trial of twice repeated injections of 50 units of BTA or placebo in the bulbocavernosus muscles, 3 months apart, in women with PVD. Treatment outcome after six months’, failed to show any significant difference in pain reduction between the groups, as previously reported. Here, we report treatment outcomes 12 months after the first injections. In addition to injections, participants where instructed to perform pelvic floor exercises during month 6-12. 38 participants/group was calculated to achieve a statistical power of 80% based on an effect size of 20 VAS units (mean score range 56-76±31 SD). Outcomes: Primary outcome was self-reported dyspareunia or pain at tampon use, using a visual analogue scale (VAS) 0-100. Secondary outcomes were vaginal pressure measurements, psychological health, sexual function and distress. Results: From the initial 88 randomized women with PVD, 75 remained at 12 months; 38 in the BTA and 37 in the placebo group. There was no significant difference in primary outcome between the groups. Vaginal pressure in the BTA group had been restored to pre-treatment levels, with no differences between the groups at 12 months. There was an increase in sexual function in the BTA group, with a Female Sexual Function Index of 22.8 (±4.8) compared to the placebo group to 19.7 (±5.0), P=.048. No differences were observed in sexual distress, stress and anxiety. There was an increase in number of women attempting intercourse in the BTA group (74%) compared with placebo (43%), P=.005. Too few patients performed the pelvic floor exercises for this intervention to be analyzed. Clinical Implications: This study highlights BTA as a safe treatment option for patients with PVD. Strengths and limitations: The randomized, double-blinded design and repeated treatments are the major strengths of this study and it is the first study to objectively evaluate muscular effect after BTA injections. The major shortcoming is that few participants performed the pelvic floor exercises, preventing analyses. Conclusion: At 12 months’ follow up, no significant difference in reduction of dyspareunia or pain at tampon use was observed. Women receiving BTA attempted intercourse more often and improved their sexual function compared with women receiving placebo. Haraldson P, Mühlrad H, Heddini U, et al. Botulinum Toxin A for Provoked Vestibulodynia: 12 Months’ Follow-up of a Randomized Controlled Trial. J Sex Med 2022;19:1670–1679.
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| 7. |
- Heddini, Ulrika
(författare)
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Provoked vestibulodynia : studies on pain genetics and pain co-morbidity
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective: The purpose of this thesis was to investigate a possible genetic predisposition for developing provoked vestibulodynia (PVD), focusing on previously defined single nucleotide polymorphisms (SNPs) in three genes with a known influence on endogenous pain modulation: GCH1, OPRM1 and 5HT-2A. We also investigated the effects of any potential interactions between these SNPs and the use of hormonal contraceptives, serum levels of β-endorphin and symptoms of anxiety and depression, on the risk of developing PVD and general pain sensitivity. Potential predictors of treatment outcome and the prevalence of pain co-morbidity among women with PVD were also explored. Materials and methods: The thesis is based on one descriptive study and three case-control studies which included 109 women with PVD and 103 healthy controls who underwent quantitative sensory testing and filled out study-specific questionnaires. Venous blood samples were collected for genetic analyses and β-endorphin quantification. Results: The results showed that the probability of being diagnosed with PVD was elevated in carriers of the 118A genotype (rs1799971) of the OPRM1 gene (OR 1.8) and the 102C genotype (rs6313 ) of the 5HT-2A gene (OR 2.9) but not in carriers of the studied SNPs in the GCH1 gene (rs8007267, rs3783641 and rs10483639). However, there appeared to be an interactive effect between the GCH1 SNPs and use of hormonal contraceptives, with respect to pain sensitivity among women who were currently receiving treatment for PVD. There was increased pressure pain sensitivity among participants carrying the 118A genotype of the OPRM1 gene and those with PVD were more sensitive than healthy controls to pressure pain and had higher levels of plasma β-endorphin. The probability for PVD was also elevated among participants with symptoms of anxiety (OR 5.2). Higher prevalence of concomitant bodily pain was correlated with the 102C genotype of the 5HT-2A gene and with anxiety. A successful treatment outcome was more likely in women with PVD who had fewer other concomitant pain conditions and in those with secondary PVD. The number of other bodily pain conditions was also associated with the intensity of coital pain. Conclusions: The results of these studies indicate that specific genetic polymorphisms in the opioid and serotonin systems that affect endogenous pain modulation contribute to the risk of developing PVD. This substantiates the findings of earlier studies, which found greater general pain sensitivity and more anxiety symptoms in patients than in controls. Women with PVD who had more pronounced general pain dysfunction and those who had primary PVD were less likely to achieve a satisfactory treatment outcome. These findings strengthen the concept that PVD is a general pain condition. Clinical implications: It is proposed that a careful medical history be carried out in women with PVD to investigate the degree of concomitant pain disorders and to establish the subgroup of PVD so as to identify patients who could benefit from referral to specialist centers. Early recognition and treatment of the disorder could, in addition to restoring the sexual health of the affected women, also prevent aggravated chronic pain problems in this patient group.
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