Neuropathy and pain after breast cancer treatment: a prospective observational study.

OBJECTIVES: Neurological complications including pain are common after treatment for breast cancer. This prospective study investigated the symptoms, intensity and interference of chemotherapy-induced peripheral neuro-pathy. (CIPN) in the feet and hands compared to surgery- and radiation-induced neuropathy in the breast and upper arm. METHODS: Consecutive patients referred to surgery for breast cancer were included in a prospective study and completed a questionnaire at baseline and a follow-up questionnaire and interview after one year. CIPN was assessed with the CIPN20 questionnaire and the Michigan Neuropathy Screening Instrument questionnaire (MNSIq). Pain intensity was rated on a numeric rating scale (NRS, 0-10). RESULTS: In total 144 patients were included, of which 73 received chemotherapy. At one-year follow-up, symptoms of polyneuropathy were more common in patients treated with chemotherapy. Tingling or numbness in the feet in those treated/not treated with chemotherapy was reported by 44 (62%) and 15 (21%), respectively. Pain was present in 22 (30%) and 10 (14%), respectively. Pain in the area of surgery was reported by 66 (46%). Although less common, pain in the feet in those treated with chemotherapy was rated as more intense and with more daily life interference than pain in the surgical area (NRS 5.5 (SD 1.9) vs. 3.1 (SD 1.9). CONCLUSIONS: Neurological complications including pain following surgery and chemotherapy represent a burden to breast cancer survivors. In those who had received chemotherapy, pain in the feet was less common than pain in the surgical area, but pain in the feet was more intense and had a higher interference with daily life. Our study emphasizes the need for either baseline data or a control population for improved estimation of the presence and severity of CIPN and pain from questionnaires.

Correction: Predictors of opioid efficacy in patients with chronic pain: A prospective multicenter observational cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0171723.].

Corneal confocal microscopy as a tool for detecting diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes: ADDITION-Denmark.

AIMS: In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes. METHODS: CCM, nerve conduction studies, and assessment of symptoms and clinical deficits of DPN were undertaken in 144 participants with type 2 diabetes and 25 controls. DPN was defined according to the Toronto criteria for confirmed DPN. RESULTS: Corneal nerve fiber density (CNFD) was lower both in participants with confirmed DPN (n = 27) and in participants without confirmed DPN (n = 117) compared with controls (P = 0.04 and P = 0.01, respectively). No differences were observed for CNFD (P = 0.98) between participants with and without DPN. There were no differences in CNFL and CNBD between groups (P = 0.06 and P = 0.29, respectively). CNFD was associated with age, height, total- and LDL cholesterol. CONCLUSIONS: CCM could not distinguish patients with and without neuropathy, but CNFD was lower in patients with type 2 diabetes compared to controls. Age may influence the level of CCM measures.

Pain and sensory disturbances following surgical repair of pectus carinatum.

BACKGROUND/PURPOSE: The purpose of this study was to assess the characteristics of persistent postoperative pain and sensory disturbances following surgical repair of pectus carinatum. METHODS: Using a prospective observational design, 28 patients were assessed before, 6 weeks and 6 months after a modified Ravitch operation for pectus carinatum. Postoperative pain was assessed using the Short Form McGill Pain Questionnaire. Sensory testing was conducted to detect brush-evoked allodynia and pinprick hyperalgesia. Additionally, generic and disease-specific quality of life was assessed using the Short Form-36 Health Survey and the Nuss Questionnaire Modified for Adults before and after surgery. RESULTS: Six weeks after surgery, ten patients reported mild pain or discomfort. Six months after surgery, four patients reported only mild pain. Allodynia was detected in two patients 6 weeks and 6 months after surgery. Hyperalgesia was detected in eight patients 6 weeks after surgery, and in six patients 6 months after surgery. Generic quality of life was significantly improved over time. CONCLUSIONS: The study showed no significant pain problems, a tendency to reduced sensory disturbances and significant improvements in quality of life 6 months after surgical repair of pectus carinatum. Future studies should include a longer follow-up period to determine if these positive results are persistent. LEVELS OF EVIDENCE: 1 (Prognosis Study).

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain.

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Predictors of opioid efficacy in patients with chronic pain: A prospective multicenter observational cohort study.

Opioids are increasingly used for treatment of chronic pain. However, they are only effective in a subset of patients and have multiple side effects. Thus, studies using biomarkers for response are highly warranted. The current study prospectively examined 63 opioid-naïve patients initiating opioid use for diverse types of chronic pain at five European centers. Quantitative sensory testing, electroencephalography (EEG) recordings, and assessment of pain catastrophizing were performed prior to treatment. The co-primary outcomes were change from baseline in ratings of chronic pain and quality of life after 14 days of opioid treatment. Secondary outcomes included patient's global impression of clinical change and side effects. Logistic regression models adjusted for age and sex were used to identify biomarkers predictive for successful treatment, defined as at least a 30% reduction in average pain intensity or an improvement in quality of life of at least 10 scale points. Fifty-nine patients (94%) completed the study. The mean age was 55 ± 16 years and 69% were females. Pain reduction was predicted by cold pain intensity (OR: 0.69; P = 0.01), pain catastrophizing (OR: 0.82; P = 0.03), relative delta (OR: 0.76; P = 0.03) and beta EEG activity (OR: 1.18; P = 0.04) induced by experimental cold pain. None of the study variables were related to improvement in quality of life. For the first time, individual pain processing characteristics have been linked to opioid response in a mixed chronic pain population. This has the potential to personalize treatment of chronic pain and restrict opioid use to patients with high likelihood for response.

Situational but Not Dispositional Pain Catastrophizing Correlates With Early Postoperative Pain in Pain-Free Patients Before Surgery.

UNLABELLED: Pain catastrophizing may be assessed as a dispositional measure using a previous painful experience as a reference or as a situational measure using an actual ongoing pain as a reference. The latter has shown more robust correlations with pain-related outcomes; the relative influence of dispositional and situational pain catastrophizing remains unknown in relation to populations with no pain before surgery. Forty-two consecutive patients who underwent corrective surgery for funnel chest were asked to complete the Pain Catastrophizing Scale with reference to 1) a previous painful experience (dispositional pain catastrophizing), 2) experimental pain during a 2-minute cold pressor test (situational experimental pain catastrophizing), and 3) clinical pain 3 days after surgery (situational clinical pain catastrophizing) to investigate whether these measures predicted immediate pain intensity and unpleasantness in the early postoperative period. Thirty-four patients were available for analyses. Dispositional pain catastrophizing was unrelated to situational experimental and situational clinical pain catastrophizing and to postoperative pain and unpleasantness (P > .05). In contrast, the 2 situation-specific pain catastrophizing measures were strongly associated (ρ = .59, P = .0002). In analyses adjusted for preoperative anxiety, depression, and cold pressor pain sensitivity, situational experimental and situational clinical pain catastrophizing correlated with postoperative movement-evoked pain (ß = 1.36, P = .01 and ß = 1.24, P = .02, respectively) and unpleasantness (ß = 1.32, P = .01 and ß = 1.36, P = .01, respectively). PERSPECTIVE: Pain catastrophizing should be captured in relation to specific painful events in otherwise healthy patients. Future studies might benefit from assessing situational pain catastrophizing to identify patients at risk for increased postoperative pain to optimize stratified pain treatment.

Surgical correction of pectus carinatum improves perceived body image, mental health and self-esteem.

PURPOSE: The purpose of this study was to assess the effects of surgical correction of pectus carinatum on health-related quality of life and self-esteem. METHODS: Between May 2012 and May 2013, a prospective observational single-center cohort study was conducted on consecutive patients undergoing surgical correction of pectus carinatum at our institution. Patients filled in questionnaires on health-related quality of life and self-esteem before and six months after surgery. RESULTS: Disease-specific health-related quality of life was improved by 33% (95% CI: 23; 44%) according to responses to the Nuss Questionnaire modified for Adults. The improvement for generic mental health-related quality of life was 7% (95% CI: 3; 12%) in responses to the Short Form-36 Questionnaire. The improvement in self-esteem was 9% (95% CI: 2; 17%) as assessed with the Rosenberg Self-Esteem Scale. A Single Step Questionnaire supported the improvements in health-related quality of life and self-esteem six months postsurgery. CONCLUSION: This study confirms positive effects of surgical correction of pectus carinatum on health-related quality of life and self-esteem. Patients were to a greater extent self-satisfied about chest appearance following surgery, indicating this to be a step in the right direction toward improved body image, mental health and self-esteem.

Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions.

Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments.

Conditioned pain modulation and situational pain catastrophizing as preoperative predictors of pain following chest wall surgery: a prospective observational cohort study.

BACKGROUND: Variability in patients' postoperative pain experience and response to treatment challenges effective pain management. Variability in pain reflects individual differences in inhibitory pain modulation and psychological sensitivity, which in turn may be clinically relevant for the disposition to acquire pain. The aim of this study was to investigate the effects of conditioned pain modulation and situational pain catastrophizing on postoperative pain and pain persistency. METHODS: Preoperatively, 42 healthy males undergoing funnel chest surgery completed the Spielberger's State-Trait Anxiety Inventory and Beck's Depression Inventory before undergoing a sequential conditioned pain modulation paradigm. Subsequently, the Pain Catastrophizing Scale was introduced and patients were instructed to reference the conditioning pain while answering. Ratings of movement-evoked pain and consumption of morphine equivalents were obtained during postoperative days 2-5. Pain was reevaluated at six months postoperatively. RESULTS: Patients reporting persistent pain at six months follow-up (n = 15) were not significantly different from pain-free patients (n = 16) concerning preoperative conditioned pain modulation response (Z = 1.0, P = 0.3) or level of catastrophizing (Z = 0.4, P = 1.0). In the acute postoperative phase, situational pain catastrophizing predicted movement-evoked pain, independently of anxiety and depression (ß = 1.0, P = 0.007) whereas conditioned pain modulation predicted morphine consumption (ß = -0.005, P = 0.001). CONCLUSIONS: Preoperative conditioned pain modulation and situational pain catastrophizing were not associated with the development of persistent postoperative pain following funnel chest repair. Secondary outcome analyses indicated that conditioned pain modulation predicted morphine consumption and situational pain catastrophizing predicted movement-evoked pain intensity in the acute postoperative phase. These findings may have important implications for developing strategies to treat or prevent acute postoperative pain in selected patients. Pain may be predicted and the malfunctioning pain inhibition mechanism as tested with CPM may be treated with suitable drugs augmenting descending inhibition.

Perioperative gabapentin for the prevention of persistent pain after thoracotomy: a randomized controlled trial.

OBJECTIVES: To evaluate the effect of perioperative gabapentin treatment for the prevention of persistent post-thoracotomy pain and to establish whether gabapentin has a significant therapeutic impact on acute postoperative pain. METHODS: Consecutive patients with pulmonary malignancies scheduled for anterior thoracotomy were enrolled in this randomized, double-blinded, placebo-controlled trial. Patients were given 1200 mg gabapentin or placebo 2 h before surgery followed by increasing doses during 5 postoperative days: 600 mg for day 1; 900 mg for day 2; and 1200 mg for days 3-5. Effective pain relief was provided with perioperative multimodal analgesia with epidural infusion of bupivacaine and morphine for 72 h, and oral acetaminophen, ibuprofen and morphine. The main outcome was persistent post-thoracotomy pain at 6 months. Secondary outcomes included measures of early postoperative post-thoracotomy pain, morphine requirements, recovery and analgesia-related adverse effects over the first 3 weeks as well as persistent post-thoracotomy pain at 3 months. RESULTS: A total of 104 patients were randomly assigned to the intervention or control group; 86 (83%) patients were available for the 14-day analysis, 76 (73%) for the 3-month analysis and 67 (64%) for the 6-month follow-up. At 6 months postoperatively, 47% of patients treated with gabapentin reported persistent post-thoracotomy pain compared with 49% in the placebo group (P = 0.9). No overall clinically or statistically significant differences were observed between groups receiving placebo and gabapentin, respectively, for the secondary outcome measures and treatment-related adverse events. CONCLUSIONS: We found no evidence for the superiority of gabapentin over placebo for the treatment of acute pain following thoracotomy or for the prevention of persistent post-thoracotomy pain.

Persistent post-surgical pain following anterior thoracotomy for lung cancer: a cross-sectional study of prevalence, characteristics and interference with functioning.

OBJECTIVES: Most studies of persistent post-surgical pain following thoracic surgery have focused on classic posterolateral thoracotomy in mixed surgical populations without systematic assessment of disease recurrence and other potential sources of pain. The purpose of this study was to examine patterns in the prevalence of persistent post-surgical pain following lung cancer surgery and to quantitatively assess the characteristics of persistent post-surgical pain and associated sensory changes. METHODS: In May 2010, a sample of 702 patients undergoing lung cancer surgery from 1 January 2000 to 31 December 2009 was asked to complete a mail distributed questionnaire. The questionnaire included the Brief Pain Inventory and questions on pain-associated characteristics, symptoms and sensory changes. Patients were enrolled according to the following criteria: (1) no additional surgical procedures performed in the thoracic region 10 years prior to and up until the cross section; (2) no explorative surgery; (3) no resection of the thoracic wall and (4) no clinical or radiological signs of disease recurrence. Patients undergoing video-assisted thoracoscopic surgery were excluded. RESULTS: The response rate was 89%. The final study population consisted of 414 patients with a median age of 69 years and a median follow-up time of 45 months. The overall prevalence of persistent post-surgical pain following anterior thoracotomy was estimated to 19% (95% CI: 15-23%). Clinically relevant pain defined as ≥4 on a 0-10 numerical rating scale was prevalent in 9% of the study participants (95% CI: 6-12%); pain with neuropathic characteristics was present in 36% (95% CI: 25-48%). A total of 62% of the participants with persistent post-surgical pain reported an increased or decreased sense of touch in the painful area. CONCLUSIONS: Persistent post-surgical pain following anterior thoracotomy was prevalent in 19% (95% CI: 15-23%) of lung cancer patients for up to 10 years postoperatively. Future preventive strategies should focus on the role of intraoperative nerve damage, including the potentially protective role of anterior thoracotomy.

Placebo manipulations reduce hyperalgesia in neuropathic pain.

Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

Postoperative consumption of opioid analgesics following correction of pectus excavatum is influenced by pectus severity: a single-centre study of 236 patients undergoing minimally invasive correction of pectus excavatum.

OBJECTIVE: Surgical correction of pectus excavatum (PE) is primarily performed to achieve cosmetic and psychological benefits for the patient. Minimally invasive repair of PE is often associated with severe postoperative pain. This study estimates the effect of the severity of PE on the postoperative consumption of opioid analgesics following this procedure to optimise pain management. METHODS: A retrospective study was conducted on 236 consecutive patients undergoing minimally invasive repair of PE from 2005 to 2008. The collected data included depth of preoperative pectus excavation, patient demographics, peri- and postoperative information, including data on pain management. The consumption of opioid analgesics was registered after discontinuation of epidural analgesia and other types of opioid analgesics used during the study period were converted to morphine equivalents. Multiple linear regression analysis was performed to estimate the effect of the severity of PE on the postoperative consumption of opioid analgesics and to adjust for potential confounding. RESULTS: The total morphine consumption following minimally invasive repair of PE ranged between 20 and 370 mg day(-1). Multiple linear regression analysis explained approximately 30% of the variation in daily morphine consumption (R-squared=0.2957). There was a significant positive linear relationship between pectus severity and the daily consumption of morphine. Thus, postoperative consumption of morphine increased by 6% (95% confidence interval (CI): 0.3-11%) when preoperative PE depth deteriorated with 1cm. CONCLUSION: This study confirms that pectus severity has a significant impact on the consumption of opioid analgesics following minimally invasive repair of PE. We conclude that knowledge of pectus severity might be useful in the prediction of the expected morphine consumption in future patients, especially during the critical transition period from epidural analgesia to oral analgesia.