Effect of Catechol-o-methyltransferase-gene (COMT) Variants on Experimental and Acute Postoperative Pain in 1,000 Women undergoing Surgery for Breast Cancer

Abstract Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. Methods: Intensity of cold (+2-4°C) and heat (+48°C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression. Results: There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found. Conclusions: SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied.

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Pain in 1,000 Women Treated for Breast Cancer

Anesthesiology ◽

10.1097/aln.0000000000000012 ◽

2013 ◽

Vol 119 (6) ◽

pp. 1410-1421 ◽

Cited By ~ 62

Author(s):

Mari A. Kaunisto ◽

Ritva Jokela ◽

Minna Tallgren ◽

Oleg Kambur ◽

Emmi Tikkanen ◽

...

Keyword(s):

Breast Cancer ◽

Chronic Pain ◽

Postoperative Pain ◽

Postoperative Analgesia ◽

Pain Sensitivity ◽

Experimental Pain ◽

Interindividual Variation ◽

Weak Correlation ◽

Acute Postoperative Pain ◽

Cold Pain

Abstract Background: This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. Methods: One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. Results: The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4–5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. Conclusions: Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain. In a study of 1,000 women undergoing breast surgery for cancer, a small portion of the variance in preoperative response to noxious heat and cold testing could be explained by anxiety, the presence of chronic pain, and the number of previous operations. There was a weak correlation between response to experimental pain testing and acute postoperative pain, with largely similar predictive factors across both.

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Prediction of Acute Postoperative Pain Following Breast Cancer Surgery Using the Pain Sensitivity Questionnaire

Clinical Journal of Pain ◽

10.1097/ajp.0000000000000380 ◽

2017 ◽

Vol 33 (1) ◽

pp. 57-66 ◽

Cited By ~ 18

Author(s):

Benno Rehberg ◽

Stanislas Mathivon ◽

Christophe Combescure ◽

Yannick Mercier ◽

Georges L. Savoldelli

Keyword(s):

Breast Cancer ◽

Postoperative Pain ◽

Pain Sensitivity ◽

Cancer Surgery ◽

Breast Cancer Surgery ◽

Acute Postoperative Pain

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Postoperative oxycodone in breast cancer surgery: What factors associate with analgesic plasma concentrations?

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2016.05.009 ◽

2016 ◽

Vol 12 (1) ◽

pp. 118-119

Author(s):

Kristiina Cajanus ◽

Mikko Neuvonen ◽

Mari Kaunisto ◽

Outi Koskela ◽

Pertti J. Neuvonen ◽

...

Keyword(s):

Breast Cancer ◽

Postoperative Pain ◽

Pain Intensity ◽

Demographic Data ◽

Geometric Mean ◽

Plasma Concentrations ◽

Cancer Surgery ◽

Breast Cancer Surgery ◽

Satisfactory Analgesia ◽

Type Of Surgery

AbstractAimsParenteral oxycodone is increasingly used worldwide to manage perioperative pain. Oxycodone doses required for adequate analgesia vary significantly between individuals. Our study investigated whether an analgesic plasma concentration could be determined for oxycodone and which factors affect it.Methods1000 women undergoing breast cancer surgery were recruited to the study. Demographic data were collected and their cold and heat pain sensitivity and anxiety scores were measured preoperatively. After surgery, rest and motion pain intensities were measured. Intravenous oxycodone was administered until the patients reported satisfactory pain relief (NRS <4/10). At this point, plasma concentrations of oxycodone and its metabolites were determined. A second plasma sample for oxycodone deter-mination was taken when the patient requested a new dose of oxycodone. Genomic DNA was extracted from whole blood samples and the patients were genotyped for CYP2D6, CYP3A4 and CYP3A5 variants.ResultsThe two oxycodone concentrations showed a strong correlation (r =0.84). The pain intensity measured during motion before oxycodone dosing correlated significantly with the plasma oxycodone concentration (geometric mean 35.3 ng/ml and CV % 66.4) required to achieve satisfactory analgesia (r = 0.38, p = 1.5 x 10-33). The most important factors associating with postoperative pain intensity were type of surgery (breast conserving or mastectomy with or without axillary clearance) and the age of the patient. Older patients reported lower pain scores and required smaller oxycodone concentrations for satisfactory analgesia. CYP2D6, CYP3A5 or CYP3A4 genotypes did not significantly affect the oxycodone concentrations, but CYP2D6 genotype significantly affected the formation of the metabolites oxymorphone and noroxymorphone. CYP3A4 and CYP3A5 genotypes did not affect the metabolite formation.ConclusionsOur results indicate that the more pain the patient experiences postoperatively the greater her minimum plasma oxycodone concentration must be to achieve satisfactory analgesia. Type of surgery and age significantly affect postoperative pain intensity.

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Validation of the Numerical Rating Scale for Pain Intensity and Unpleasantness in Pediatric Acute Postoperative Pain: Sensitivity to Change Over Time

Journal of Pain ◽

10.1016/j.jpain.2011.12.010 ◽

2012 ◽

Vol 13 (4) ◽

pp. 359-369 ◽

Cited By ~ 87

Author(s):

M. Gabrielle Pagé ◽

Joel Katz ◽

Jennifer Stinson ◽

Lisa Isaac ◽

Andrea L. Martin-Pichora ◽

...

Keyword(s):

Postoperative Pain ◽

Pain Intensity ◽

Pain Sensitivity ◽

Rating Scale ◽

Numerical Rating Scale ◽

Sensitivity To Change ◽

Acute Postoperative Pain ◽

Change Over Time ◽

Numerical Rating ◽

Over Time

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Genetic variation in P2RX7 and pain

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2016.05.030 ◽

2016 ◽

Vol 12 (1) ◽

pp. 127-127

Author(s):

O. Kambur ◽

K. Cajanus ◽

M. Kaunisto ◽

Bendik Winsvold ◽

Audun Stubhaug ◽

...

Keyword(s):

Postoperative Pain ◽

Pain Intensity ◽

Cold Pressor Test ◽

Cold Pressor ◽

Breast Cancer Surgery ◽

Bacterial Invasion ◽

Tissue Remodelling ◽

Noxious Heat ◽

Cross Sectional ◽

Cold Pain

Abstract Background and aims P2X7 is a purinoceptor and non-selective cation channel that is activated by extracellular ATP, especially in immune and glia cells. Activation of P2X7 triggers the secretion of several pro-inflammatory substances, such as IL- 1P, IL-18, TNF-α, and nitric oxide. P2X7 activation contributes to the pro-inflammatory response to injury or bacterial invasion and mediates apoptosis. It has been implicated in physiological and pathological conditions such as bone tissue remodelling, inflammation, oncogenesis, depression, and inflammatory, neuropathic and chronic pain. Here, we aim to characterize the effects of variation within the P2RX7 gene, which encodes the P2X7 receptor, on pain and opioid requirements in human patients. Methods Pain was assessed in Norwegian and Finnish cohorts. The Norwegian cohort represents the 6th wave of the Tromsø Study, a longitudinal and cross-sectional population based study (N = 3700), whereas the Finnish cohort (BrePainGen) consists of patients who underwent breast cancer surgery (N = 1000). For both cohorts, experimental pain data were analyzed. Pain intensity and tolerance were assessed with cold pressor test and after standardized noxious heat stimulation in both cohorts. In addition, data on acute postoperative pain and opioid requirements were analyzed in the BrePainGen cohort. Postoperative pain and opioid responses were followed during 20 h after surgery. In total, 29 single nucleotide polymorphisms (SNPs) in P2RX7 were genotyped and their association with outcome variables was assessed using linear regression and analysis of variances (ANOVA). Results Several P2RX7 SNPs were associated with the pain phenotypes. The strongest associations were seen with cold pain intensity and tolerance. The results of this study will be presented at the meeting. Conclusions Our results suggest that P2X7 and genetic varia-tion in the P2RX7-gene are involved in the modulation of human pain responses.

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Prevention of Acute Postoperative Pain in Breast Cancer: A Comparison between Opioids versus Ketamine in the Intraoperatory Analgesia

Pain Research and Management ◽

10.1155/2021/3290289 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Mirian López ◽

María Luz Padilla ◽

Blas García ◽

Javier Orozco ◽

Ana María Rodilla

Keyword(s):

Breast Cancer ◽

Postoperative Pain ◽

Rating Scale ◽

Numeric Rating Scale ◽

Cancer Surgery ◽

Breast Cancer Surgery ◽

Opioid Use ◽

Acute Postoperative Pain ◽

Systemic Side Effects ◽

Waking Up

Background. Acute postoperative pain (APP) has a high incidence in breast surgery, and opioids are the most commonly used drugs for its management; however, they are not free from systemic side effects, which may increase comorbidity. In the past few years, opioid-free anaesthesia has been favoured with promising results. Methods. We conducted a descriptive study including 71 patients who underwent breast cancer surgery. The opioid group (n = 41) received fentanyl for induction, remifentanil for maintenance, and rescue morphine before waking up, whereas the ketamine group (n = 30) received a ketamine bolus for induction followed by continuous ketamine infusion during surgery. Later, the presence and intensity of pain were registered, using the Numeric Rating Scale (NRS 1–10) for pain, at different times in the recovery room, at 24 hours and at 3 months. Results. Administration of ketamine is more effective than opioid use for APP prevention in breast cancer surgery because the ketamine group presented with less pain than the opioid group ( p < 0.05) at all measured times. When there was pain, patients in the ketamine group gave a lower score to its intensity ( p < 0.05). Conclusions. Ketamine could reduce the incidence of APP in breast cancer surgery, compared to opioids.

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Chronic Breast Pain Prior to Breast Cancer Surgery Is Associated with Worse Acute Postoperative Pain Outcomes

Journal of Clinical Medicine ◽

10.3390/jcm10091887 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1887

Author(s):

Marium M. Raza ◽

Ruth Zaslansky ◽

Debra B. Gordon ◽

Jeanne M. Wildisen ◽

Marcus Komann ◽

...

Keyword(s):

Breast Cancer ◽

Chronic Pain ◽

Postoperative Pain ◽

Cancer Surgery ◽

Pain Interference ◽

Breast Cancer Surgery ◽

Breast Pain ◽

Acute Postoperative Pain ◽

Pain Outcomes ◽

Chronic Breast Pain

Acute postoperative pain is associated with adverse short and long-term outcomes among women undergoing surgery for breast cancer. Previous studies identified preexisting pain as a predictor of postoperative pain, but rarely accounted for pain location or chronicity. This study leveraged a multinational pain registry, PAIN OUT, to: (1) characterize patient subgroups based on preexisting chronic breast pain status and (2) determine the association of preexisting chronic pain with acute postoperative pain-related patient-reported outcomes and opioid consumption following breast cancer surgery. The primary outcome was a composite score comprising the mean of pain intensity and pain interference items from the International Pain Outcomes Questionnaire. The secondary outcome was opioid consumption in the recovery room and ward. Among 1889 patients, we characterized three subgroups: no preexisting chronic pain (n = 1600); chronic preexisting pain elsewhere (n = 128) and; chronic preexisting pain in the breast with/without pain elsewhere (n = 161). Controlling for covariates, women with preexisting chronic breast pain experienced more severe acute postoperative pain and pain interference (β = 1.0, 95% CI = 0.7-1.3, p < 0.001), and required higher doses of opioids postoperatively (β = 2.7, 95% CI = 0.6–4.8, p = 0.013). Preexisting chronic breast pain may be an important risk factor for poor pain-related postoperative outcomes. Targeted intervention of this subgroup may improve recovery.

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Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments

Scandinavian Journal of Pain ◽

10.1515/sjpain-2020-0013 ◽

2020 ◽

Vol 20 (4) ◽

pp. 683-691

Author(s):

Laura Mustonen ◽

Tommi Aho ◽

Hanna Harno ◽

Eija Kalso

Keyword(s):

Breast Cancer ◽

Neuropathic Pain ◽

Psychological Factors ◽

Mechanical Allodynia ◽

Cold Pressor Test ◽

Pain Tolerance ◽

Cancer Surgery ◽

Breast Cancer Surgery ◽

Cold Pain ◽

Static Mechanical

AbstractObjectivesStatic mechanical allodynia (SMA), i. e., pain caused by normally non-painful static pressure, is a prevalent manifestation of neuropathic pain (NP). Although SMA may significantly affect the patient’s daily life, it is less well studied in the clinical context. We aimed to characterize SMA in women with chronic post-surgical NP (CPSNP) after breast cancer surgery. Our objective was to improve understanding of the clinical picture of this prevalent pain condition. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery (Mustonen et al. Pain. 2019;160:246–56).MethodsWe studied SMA in 132 patients with CPSNP after breast cancer surgery. The presence, location, and intensity of SMA were assessed at clinical sensory examination. The patients gave self-reports of pain with the Brief Pain Inventory (BPI). We studied the association of SMA to type of surgery, oncological treatments, BMI, other pains, and psychological factors. General pain sensitivity was assessed by the cold pressor test.ResultsSMA was prevalent (84%) in this cohort whereas other forms of allodynia were scarce (6%). Moderate-to-severe SMA was frequently observed even in patients who reported mild pain in BPI. Breast and the side of chest were the most common locations of SMA. SMA was associated with breast surgery type, but not with psychological factors. Severe SMA, but not self-reported pain, was associated with lower cold pain tolerance.ConclusionsSMA is prevalent in post-surgical NP after breast cancer surgery and it may represent a distinct NP phenotype. High intensities of SMA may signal the presence of central sensitization.ImplicationsSMA should be considered when examining and treating patients with post-surgical NP after breast cancer surgery.

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