Staircase-evoked Pain May be More Sensitive Than Traditional Pain Assessments in Discriminating Analgesic Effects: A Randomized, Placebo-controlled Trial of Naproxen in Patients With Osteoarthritis of the Knee.

OBJECTIVES: Analgesic trials often fail to show a significant effect even when medications with known efficacy are tested. This could be attributed to insufficient assay sensitivity of analgesic trials, which may be due, in part, to the insensitivity of pain-related outcome measures. The aim of this methodological study was to assess the responsiveness of evoked pain generated by the staircase procedure compared with other commonly used pain outcomes in knee osteoarthritis. METHODS: This was a randomized, double-blind, placebo-controlled, cross-over trial of 1-week treatment of naproxen versus placebo. Participants were assigned to one of the 2 treatment sequences (naproxen-placebo or placebo-naproxen). Pain-at-rest, evoked pain using the Staircase-Evoked Pain Procedure (StEPP), pain diary, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) data were collected before and at the end of each treatment sequence. RESULTS: A total of 55 osteoarthritis patients (30 M, 25 F) completed the study. Among all pain assessments, evoked pain was the most sensitive outcome to detect treatment effects, with Standardized Effect Size (SES) of 0.47 followed by the WOMAC and pain-at-rest with SES of 0.43 and 0.36, respectively. Sample size calculations demonstrated that compared with spontaneous pain, the evoked pain model reduces required number of subjects by 40%. DISCUSSION: Study results support our hypothesis that evoked pain using the StEPP may demonstrate greater responsiveness to treatment effects compared with traditional pain-related outcome measures. Accordingly, these results may facilitate development and validation of other chronic pain-related evoked pain models, which could contribute to future research and development of new analgesics.

Cancer Antigen 125 Levels are Significantly Associated With Prognostic Parameters in Uterine Papillary Serous Carcinoma.

OBJECTIVES: Uterine papillary serous carcinoma (UPSC) is a highly aggressive subtype of endometrial carcinoma. Histopathologically, it resembles the pattern of serous papillary carcinoma of the ovary. Cancer antigen 125 (CA-125) is the most widely used biomarker in epithelial ovarian carcinoma. Its use in UPSC evaluation has yet to be determined. The purpose of this study was to investigate the significance of preoperative serum CA-125 as a prognostic factor in patients with UPSC. METHODS: The study cohort included all women with UPSC operated in our institution between January 2002 and June 2016. All patients underwent complete surgical staging. Preoperative CA-125 was reviewed and correlated with clinical and pathological parameters. RESULTS: Sixty-one women met the study criteria. Median preoperative CA-125 was found to be significantly associated with disease stage. Patients with disease stages I to IV had median preoperative CA-125 levels of 12.15, 19.6, 22.6, and 177.5 U/mL (P < 0.0001) respectively. Levels of CA-125 were significantly associated with positive cytology (P < 0.0001), omental disease (P < 0.0001), pelvic or para-aortic lymph node metastasis (P < 0.0001), and adnexal involvement (P < 0.0001). The optimal cutoff that provided the best sensitivity and specificity for omental and parametrial involvement as well as positive cytology was 57.5 U/mL. For adnexal and lymph node involvement, the optimal cutoff value was 41.8 U/mL. CONCLUSIONS: In patients with UPSC, preoperative CA-125 level correlates with known prognostic parameters of endometrial carcinoma and is associated with extrauterine involvement. These data should stimulate the need for further evaluation of the role of CA-125 in predicting recurrence and survival in UPSC.

The effects of a dopamine agonist (apomorphine) on experimental and spontaneous pain in patients with chronic radicular pain: A randomized, double-blind, placebo-controlled, cross-over study.

BACKGROUND: Although evidence suggests that dopaminergic systems are involved in pain processing, the effects of dopaminergic interventions on pain remains questionable. This randomized, double blinded, placebo-controlled, cross-over study was aimed at exploring the effect of the dopamine agonist apomorphine on experimental pain evoked by cold stimulation and on spontaneous pain in patients with lumbar radicular (neuropathic) pain. METHODS: Data was collected from 35 patients with chronic lumbar radiculopathy (18 men, mean age 56.2±13 years). The following parameters were evaluated before (baseline) and 30, 75 and 120 minutes subsequent to a subcutaneous injection of 1.5 mg apomorphine or placebo: cold pain threshold and tolerance in the painful site (ice pack, affected leg) and in a remote non-painful site (12°C water bath, hand), and spontaneous (affected leg) pain intensity (NPS, 0-100). RESULTS: One-hundred and twenty minutes following apomorphine (but not placebo) injection, cold pain threshold and tolerance in the hand increased significantly compared to baseline (from a median of 8.0 seconds (IQR = 5.0) to 10 seconds (IQR = 9.0), p = 0.001 and from a median of 19.5 seconds (IQR = 30.2) to 27.0 seconds (IQR = 37.5), p<0.001, respectively). In addition, apomorphine prolonged cold pain tolerance but not threshold in the painful site (from a median of 43.0 seconds (IQR = 63.0) at baseline to 51.0 seconds (IQR = 78.0) at 120 min, p = 0.02). Apomorphine demonstrated no superiority over placebo in reducing spontaneous pain intensity. CONCLUSION: These findings are in line with previous results in healthy subjects, showing that apomorphine increases the ability to tolerate cold pain and therefore suggesting that dopaminergic interventions can have potential clinical relevance.

Does self-perception of sensitivity to pain correlate with actual sensitivity to experimental pain?

BACKGROUND: People often state that they are "sensitive" or "insensitive" to pain. However, the accuracy and clinical relevance of such statements is unclear. OBJECTIVE: The aim of this study was to search for associations between self-perception of sensitivity to pain and experimental pain measures, including known psychophysical inhibitory or excitatory pain paradigms. SUBJECTS AND METHODS: Subjective sensitivity to pain was reported by 75 healthy participants and included three self-perceived variables: pain threshold, pain sensitivity and pain intensity in response to a hypothetical painful event (hypothetical pain intensity [HPI]). Experimental pain measures consisted of thermal pain threshold (°C), suprathreshold thermal pain intensity (Visual Analog Scale, 0-100) and the psychophysical paradigms of conditioned pain modulation (CPM) and temporal summation (TS), representing inhibitory and excitatory pain processes, respectively. RESULTS: No significant correlations were found between self-perceived pain threshold or pain sensitivity and any of the experimental pain measures. In contrast, the reported HPI correlated with thermal pain threshold (r = -0.282; p = 0.014), suprathreshold thermal pain intensity (r = 0.367; p = 0.001) and CPM (r = 0.233; p = 0.044), but not with TS. CONCLUSION: Self-perception of pain sensitivity articulated by intangible expressions such as pain threshold or pain sensitivity is unrelated to actual sensitivity to experimental pain. In contrast, when measured by intensity of a hypothetical painful event (HPI), sensitivity to pain is associated with some, but not all, experimental pain reports. Further studies are needed for better understanding of these associations and their potential clinical significance.

Methylphenidate attenuates the response to cold pain but not to aversive auditory stimuli in healthy human: a double-blind randomized controlled study.

INTRODUCTION: We recently showed that the psycho-stimulant norepinephrine-dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD). OBJECTIVES: The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MP's effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities. METHODS: This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo. RESULTS: Forty men, 26.1 ± 4.0 (mean ± SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 ± 2.6 to 5.4 ± 3.1 seconds, P = 0.001 and from 4.5 ± 2.6 to 4.3 ± 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 ± 54.0 to 73.8 ± 61.8 seconds, P = 0.001 and from 52.5 ± 53.7 sec to 57.0 ± 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters. CONCLUSION: These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli.

Clinical analgesia correlates with decline in temporal summation in response to remifentanil infusion in patients with chronic neuropathic (radicular) pain.

BACKGROUND: Animal studies have shown that in addition to their antinociceptive effects, opioids have attenuated the electrophysiological "wind-up" phenomenon. Although effects of opioids on clinical pain and on temporal summation (TS), the human correlatives of this phenomenon, have been tested repeatedly, correlations between these two parameters have not been reported so far. OBJECTIVES: To search for possible correlations between the effects of remifentanil on clinical pain intensity and on the magnitude of TS in patients with chronic pain. DESIGN: A single-blinded prospective study. SETTING: A tertiary care pain clinic. PATIENTS: Thirty-one patients (24 men) with chronic lumbar (radicular) neuropathic pain. INTERVENTION: Intervenous administration of saline followed by remifentanil infusions. MAIN OUTCOME MEASURES: Clinical pain intensity and thermal TS measured at baseline, during infusion of each drug and 20 minutes after termination of remifentnail infusion. RESULTS: Friedman test revealed statistically significant differences in the magnitudes of both clinical pain intensity and TS (x(2(3)) = 73, p < 0.001 and x(2(3)) = 11.38, p = 0.01, respectively). Post hoc analysis (Wilcoxon signed-rank test) showed significant differences between clinical pain intensities measured at all time points but significant reductions in the magnitudes of TS were found only during remifentanil compared to baseline (p = 0.014) and to saline (p = 0.019). The difference in clinical pain between saline and remifentanil positively correlated with the difference in TS measured at the same time points (Spearman's test; r = 0.444, p = 0.012). CONCLUSIONS: These results point to a possible causative relationship between TS and opioid analgesia.

Individually based measurement of temporal summation evoked by a noxious tonic heat paradigm.

BACKGROUND: A model for measuring temporal summation (TS) by tonic noxious stimulation was recently proposed. However, methodological variations between studies make it difficult to reach a consensus regarding the way TS should be applied and calculated. The present study aimed to present a calculation method of TS magnitude produced by a tonic heat model in a large cohort of healthy subjects. METHODS: Noxious heat stimulation (46.5°C/2 minutes) was applied to the forearm of 154 subjects who continuously rated pain intensity using a computerized visual analog scale. TS was calculated by "mean group" and "individual" approaches. RESULTS: A "typical" pattern of pain response, characterized by a peak pain followed by a decrease in intensity to a nadir and subsequently a progressive increase in pain scores, was exhibited by 86.4% of the subjects. Using the "mean group" and "individual" calculation approaches, the mean ± standard deviation magnitudes of TS were 31.4±27.5 and 41.0±26.0, respectively (P<0.001). Additionally, using the individualized approach, we identified a different ("atypical") response pattern among the rest of the subjects (13.6%). CONCLUSION: The results support the tonic heat model of TS for future utilization. The individualized TS calculation method seems advantageous since it better reflects individual magnitudes of TS.

Spinal cord stimulation attenuates temporal summation in patients with neuropathic pain.

Evidence has shown that electrical stimulation at the dorsal columns attenuated the "wind-up" phenomenon in dorsal horn neurons in nerve-injured rats. This study was aimed to test the effect of spinal cord stimulation (SCS) on temporal summation (TS), the clinical correlate of the wind-up phenomenon in patients with radicular leg pain. Eighteen patients with SCS implants were tested both 30 minutes after SCS activation ("ON") and 2 hours after turning it off ("OFF"), in a random order. Temporal summation was evaluated in the most painful site in the affected leg and in the corresponding area in the contralateral leg by applying a tonic painful heat stimulus (46.5°C; 120 seconds) and simultaneous recording of the perceived heat pain intensity. Patients were also requested to report their clinical pain intensity (0-100 numerical pain scale) during SCS "ON" and "OFF". The Wilcoxon signed rank test was used in the comparisons between SCS "ON" and "OFF". Spinal cord stimulation activation significantly attenuated clinical pain intensity (from 66 ± 18 to 27 ± 31, P < 0.001). In the nonpainful leg, SCS activation failed to produce an effect on TS (24 ± 20 vs 21 ± 24 in SCS "OFF" and "ON", respectively; P = 0.277). In contrast, a significant decrease in the magnitude of TS in the affected leg was observed in response to SCS activation (from 32 ± 33 to 19 ± 24; P = 0.017). These results suggest that attenuation of TS, which likely represents suppression of hyperexcitability in spinal cord neurons, is a possible mechanism underlying SCS analgesia in patients with neuropathic pain.

Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon?

Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined.

Measuring the Intensity of Chronic Pain: Are the Visual Analogue Scale and the Verbal Rating Scale Interchangeable?

OBJECTIVES: The 0 to 100 mm visual analogue scale (VAS) and the five-category verbal rating scale (VRS) are commonly used for measuring pain intensity. An open question remains as to whether these scales can be used interchangeably to allow comparisons between intensities of pain in the clinical setting or increased statistical power in pain research. METHODS: Seven hundred and ninety-six patients were requested to rate the present intensity of their chronic pain on the two scales. Spearman's rank correlation coefficients between VAS and VRS were calculated. For testing interchangeability, VAS was transformed into a discrete ordinal scale by dividing the entire VAS into five categories, either equidistantly (biased) or using frequency distributions of VAS (unbiased). We used Goodman-Kruskal's gamma and Wilson's e measures of ordinal association quantified the relationships between the transformed VAS and VRS scores and Svensson method to evaluate agreement between biased and unbiased discrete VAS and VRS scales. RESULTS: Average VAS and VRS scores were 76 ± 18 mm and "severe," respectively. Spearman's rank correlation coefficient values between continuous VAS and VRS were 0.77 to 0.85. Goodman-Kruskal's gamma ordinal associations between discrete VAS and VRS were 0.82 to 0.92 and 0.90 to 0.98 for the biased and unbiased VAS, respectively. Wilson's e measures were 0.51 to 0.61 and 0.54 to 0.65, accordingly. Svensson analysis showed low probability of agreement between both biased (0.66 to 0.76) and unbiased (0.75 to 0.82) VAS and VRS. DISCUSSION: Regardless of the relatively high Spearman correlations between original VAS and VRS, the low ordinal association and low probability of agreement between discrete VAS and VRS suggest that they are not interchangeable. Therefore, VAS and VRS should not be used interchangeably in the clinical setting or for increased statistical power in pain research.

The effect of hydromorphone therapy on psychophysical measurements of the descending inhibitory pain systems in patients with chronic radicular pain.

OBJECTIVE: Conditioned pain modulation (CPM) and offset analgesia (OA) are considered to represent paradigms of descending inhibitory pain modulation in humans. This study tested the effects of hydromorphone therapy on descending inhibitory pain modulation, as measured by changes from baseline in the magnitudes of CPM and OA. DESIGN: Prospective evaluation. SETTING: Institute of Pain Medicine, Rambam Health Care Campus. SUBJECTS: Patients with chronic radicular pain. METHODS: Thirty patients received 4 weeks of oral hydromorphone treatment at an individually titrated dose (mean ± standard deviation dose of 11.6 ± 4.8 mg/day). CPM and OA were assessed before and after hydromorphone treatment. CPM was assessed by subtracting the response to a painful phasic heat stimulus administered simultaneously with a conditioning cold pain stimulus, from the response to the same heat stimulus administered alone. The OA paradigm consisted of a three-temperature stimuli train (T1 = 49°C [5 seconds], T2 = 50°C [5 seconds], and T3 = 49°C [20 seconds]). The magnitude of OA was quantified by subtracting minimal pain scores obtained during T3 from the maximal pain scores obtained during T2. RESULTS: CPM scores changed from a baseline of 17.7 ± 20.6 to 21 ± 20.4 following treatment, and OA scores changed from 7.8 ± 20.5 to 9.7 ± 14.6. Wilcoxon signed rank test indicated that these changes were not significant (CPM: P = 0.22; OA: P = 0.44). McNemar test revealed that the percentage of patients who exhibited a change in the direction of CPM or OA in response to hydromorphone treatment was not significant (CPM: P = 0.37; OA: P = 0.48). CONCLUSIONS: These results suggest that the descending inhibitory pain modulation, as manifested in humans by CPM and OA, is unlikely to be mediated by hydromorphone therapy.

Drug combinations in the treatment of neuropathic pain.

Pharmacotherapy, the main treatment option for neuropathic pain, remains a major clinical challenge. The most commonly studied drug classes in the context of neuropathic pain-antidepressants, anticonvulsants, and opioids-have only limited efficacy and frequent dose-limiting adverse effects. Yet, most guidelines recommend monotherapy as the first line of neuropathic pain treatment. Recent understanding of neuropathic pain pathophysiology suggests that multiple mechanisms, both at the peripheral and the central nervous system levels, underlie neuropathic pain, pointing to the possibility that targeting multiple mechanisms simultaneously can improve treatment outcome. A few clinical trials using various drug combinations for neuropathic pain have already been published but yielded inconsistent results, partially due to methodological problems associated with the conduction of such trials. Nonetheless, combination therapy remains an intriguing treatment option for neuropathic pain, awaiting future high-quality validating trials.

Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia.

Opioid analgesia is mediated primarily by modulating (inhibiting and enhancing) pain mechanisms at the spinal and supraspinal levels. Advanced psychophysical paradigms of temporal summation (TS) and conditioned pain modulation (CPM) likely represent pain mechanisms at both levels. Therefore, the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans. The current randomized, double-blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects. TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli. CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone. These paradigms were tested before and at 60, 120, and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo. Repeated-measures analysis of variance revealed significant effects of oxycodone, but not placebo, on the magnitude of TS (F=7.196, P<.001). Pairwise comparisons revealed that relative to baseline, TS was significantly reduced at 60 minutes (P=.008) and at 180 minutes (P=.017) after oxycodone administration. In contrast, no significant effects of either oxycodone (F=0.871, P=.458) or placebo (F=2.086, P=.106) on the magnitude of CPM were found. These results suggest that under the current experimental conditions, oxycodone exerted spinal, rather than supraspinal, analgesic effects. Furthermore, compared with CPM, TS seems more suitable for studying the mechanisms of opioid analgesia in humans.

Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series.

BACKGROUND AND AIMS: Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-α adalimumab was assessed. METHODS: Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira(®) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. RESULTS: Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). CONCLUSION: These results suggest adalimumab, and possibly other anti-TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area.

A negative correlation between hyperalgesia and analgesia in patients with chronic radicular pain: is hydromorphone therapy a double-edged sword?

BACKGROUND: Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Yet, unconfirmed evidence suggests that chronic exposure to opioids may cause hypersensitivity to pain, a phenomenon known as opioid-induced hyperalgesia (OIH). OBJECTIVES: The current preliminary prospective study was aimed to explore the relationship between experimental OIH and clinical opioid induced analgesia (OIA) in a model of experimental OIH in patients with chronic radicular pain using intermediate-term opioid therapy. STUDY DESIGN: Prospective evaluation SETTING: Interdisciplinary Pain Clinic at a referral Health Care Campus METHODS: Thirty patients with chronic neuropathic (radicular) pain were assessed prior to and following 4 weeks of an individually titrated dose of oral hydromorphone treatment (4-20 mg/d). The assessments included an evaluation of experimental OIH by testing for heat pain intensity and cold pain tolerance and an assessment of OIA by completing pain and disability questionnaires. RESULTS: Hydromorphone was found to induce hyperalgesia, as measured by an elevation of phasic heat pain intensity (P < 0.05). At the same time, hydromorphone caused significant clinical analgesic effects. There was a notable reduction in average daily pain scores (primary analgesic outcome) of 26 Visual Analog Scale (0-100) points. A significant negative correlation was found between OIH and all OIA measures (r = -0.389, P < 0.05 for the primary analgesic outcome). Hydromorphone dosage was positively correlated with OIH (P < 0.01, r = 0.467) and negatively correlated with OIA parameters (r = -0.592, P < 0.01 for the primary analgesia outcome). LIMITATIONS: The nonrandomized, open-label, prospective evaluation. CONCLUSION: A 4-week regimen of open-label hydromorphone therapy results in a dose-dependent OIH, which negatively correlates with its analgesic effect. Future randomized, controlled, and blinded studies are needed to verify these preliminary results.