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This study compared the degree of secondary hyperalgesia and somatosensory threshold changes induced by topical capsaicin between spinal and trigeminal innervation. This crossover clinical trial included 40 healthy individuals in which 0.25 g of 1% capsaicin cream was randomly applied for 45 minutes to a circular area of 2 cm 2 to the skin covering the masseter muscle and forearm in 2 different sessions, separated by at least 24 hours and no more than 72 hours (washout period). The main outcome variables were the area of allodynia and pinprick hyperalgesia, as well as electrical and mechanical pain thresholds within the area of pinprick hyperalgesia. Mixed ANOVA models and McNemar tests were applied to the data ( p  = 0.050). The occurrence of allodynia and pinprick hyperalgesia was higher in the forearm than in the masseter ( p  < 0.050). Additionally, the areas of pinprick hyperalgesia and allodynia were larger in the forearm compared to the masseter ( p  < 0.050). The electrical and mechanical pain thresholds demonstrated a loss of somatosensory function following capsaicin application to the masseter ( p  < 0.050). However, no significant somatosensory threshold changes were observed at the forearm after capsaicin ( p  > 0.050). In conclusion, these findings indicate potential differences compatible with central sensitization related to secondary hyperalgesia between trigeminal and spinal innervation.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain ( p  = 0.7479), HPT ( p  = 0.7501), area of PMH ( p  = 0.1052) or flare size ( p  = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller ( p  < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

Remifentanil-induced hyperalgesia (RIH) increases the risk of persistent postoperative pain, making early postoperative analgesic therapy ineffective and affecting postoperative patient satisfaction. This study aimed to verify the effects of gradual withdrawal of remifentanil combined with postoperative pump infusion of remifentanil on postoperative hyperalgesia and pain in patients undergoing laparoscopic hysterectomy. This trial was a factorial design, double-blind, randomized controlled trial. Patients undergoing laparoscopic hysterectomy were randomly allocated to the control group, postoperative pump infusion of remifentanil group, gradual withdrawal of remifentanil group, or gradual withdrawal plus postoperative pump infusion of remifentanil group (n = 35 each). The primary outcome was postoperative mechanical pain thresholds in the medial forearm. The secondary outcomes included postoperative mechanical pain thresholds around the incision, pain numeric rating scale scores, analgesic utilization, awakening agitation or sedation scores, a 15-item quality of recovery survey, and postoperative complications. Gradual withdrawal of remifentanil significantly increased postoperative pain thresholds versus abrupt discontinuation ( < 0.05), whereas postoperative infusion did not show significant differences compared to the absence of infusion ( > 0.05). The combined gradual withdrawal and postoperative infusion group exhibited the highest thresholds and had the lowest postoperative pain scores and analgesic requirements as well as the highest quality of recovery scores ( < 0.05). No significant differences were observed for agitation scores, sedation scores, or complication rates ( > 0.05). The novel combined gradual withdrawal and postoperative infusion of remifentanil uniquely attenuates postoperative hyperalgesia, pain severity, analgesic necessity, and improves recovery quality after laparoscopic hysterectomy.

Abstract Objective Nerve growth factor (NGF) is essential for generating and potentiating pain responses. This double-blinded crossover study assessed NGF-evoked pain in healthy humans after repeated NGF injections in the tibialis anterior (TA) muscle compared with control injections of isotonic saline. Subjects Twenty healthy subjects participated in two experimental phases; each consisted of seven sessions over 21 days. Methods At day 0, day 2, and day 4, a low-dose NGF (1 µg) was injected. Data on daily self-reported muscle pain (using a Likert scale) were collected. Data on pressure pain thresholds (PPTs), pain evoked by nonischemic and ischemic muscle contractions (using a numerical rating scale [NRS]), pressure pain detection (PDT), and pain tolerance thresholds (PTTs) to cuff algometry were recorded before day 0 and at 1, 2, 4, 7, 10, and 21 days after the first injection. Temporal summation of pain (TSP) and conditioned pain modulation (CPM) were recorded to assess central pain mechanisms. Results Likert scores remained elevated for 9 days after NGF injection (P<0.05). PPTs at the TA muscle were decreased at day 1 until day 7 after NGF injection compared with day 0 (P=0.05). In subjects presenting with NGF-induced muscle hyperalgesia, pain NRS scores evoked by nonischemic contractions were higher after NGF injection at day 4 and day 7 (P<0.04) compared with the control condition. At all time points, higher pain NRS scores were found with ischemic compared with nonischemic contractions (P<0.05). The pain NRS after ischemic contractions was elevated following prolonged NGF hyperalgesia at day 7 compared with the control condition and day 0 (P<0.04). The PDT, PTT, TSP, and CPM remained unchanged during the period of NGF-induced hyperalgesia. Conclusions Repeated low-dose NGF injections maintain muscle pain and potentiate pain evoked by ischemic contractions during prolonged NGF hyperalgesia.

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.

Background and Objectives: The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on opioid-induced hyperalgesia (OIH) in patients undergoing general anesthesia. Materials and Methods: The patients were randomized into three groups: group RHR (6 mg/kg/h initial dose followed by 1 mg/kg/h remimazolam and 0.3 μg /kg/min remifentanil), group DHR (desflurane and 0.3 μg /kg/min remifentanil) or group DLR (desflurane and 0.05 µg/kg /min remifentanil). The primary outcome was a mechanical hyperalgesia threshold, while secondary outcomes included an area of hyperalgesia and clinically relevant pain outcomes. Results: Group RHR had a higher mechanical hyperalgesia threshold, a smaller hyperalgesia postoperative area at 24 h, a longer time to first rescue analgesia (p = 0.04), lower cumulative PCA volume containing morphine postoperatively consumed for 24 h (p < 0.01), and lower pain intensity for 12 h than group DHR (p < 0.001). However, there was no significant difference in OIH between groups RHR and DLR. Conclusions: Group RHR, which received remimazolam, attenuated OIH, including mechanically evoked pain and some clinically relevant pain outcomes caused by a high dose of remifentanil. Further research is essential to determine how clinically meaningful and important the small differences observed between the two groups are.

Abstract Objective Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting Ambulatory. Subjects Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2–22 mg); no dose change for 1.5–12 months. Ten healthy controls. Methods Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

We aimed to evaluate the regulatory effects of propofol on high-dose remifentanil-induced hyperalgesia. A total of 180 patients receiving laparoscopic cholecystectomy were randomly divided into sevoflurane + high-dose remifentanil (SH) group, sevoflurane + low-dose remifentanil (SL) group and propofol + high-dose remifentanil group (PH) group (n=60). After intravenous administration of midazolam, SH and SL groups were induced with sevoflurane and remifentanil, and PH group was induced with propofol and remifentanil. During anesthesia maintenance, SH and SL groups were given 0.3 μg/kg/min and 0.1 μg/kg/min sevoflurane and remifentanil respectively, and PH group was given 0.3 μg/kg/min propofol and remifentanil. The three groups had significantly different awakening time, extubation time and total dose of remifentanil (P<0.001). Compared with SL group, periumbilical mechanical pain thresholds 6 h and 24 h after surgery significantly decreased in SH group (P<0.05), and the visual analog scale (VAS) scores significantly increased 30 min, 2 h and 6 h after surgery (P<0.05). Compared with SH group, periumbilical mechanical thresholds 6 h and 24 h after surgery were significantly higher in PH group (P<0.05), and VAS scores 30 min, 2 h and 6 h after surgery were significantly lower (P<0.05). PH group first used patient-controlled intravenous analgesia pump significantly later than SL group did (P<0.05). The total consumptions of sufentanil in PH and SL groups were significantly lower than that of SH group (P<0.05). The incidence rates of bradycardia and postoperative chill in PH and SH groups were significantly higher than those of SL group (P<0.05). Anesthesia by infusion of high-dose remifentanil plus sevoflurane caused postoperative hyperalgesia which was relieved through intravenous anesthesia with propofol.

Inflammation and the related acidity in peri-articular structures may be involved in pain generation and hyperalgesia in knee osteoarthritis. This study investigated pain and associated hyperalgesia provoked by infusion of acidic saline into the infrapatellar fat pad. Twenty-eight subjects participated in two sessions in which acidic saline (AS, pH 5) or neutral saline (NS, pH 7.4) were infused into the infrapatellar fat pad for 15 min. Pain intensity, pain area, mechanical and thermal sensitivity, and maximal voluntary knee extension force were recorded. Repeated infusions were performed in 14 subjects. Infusion of AS caused significantly higher pain intensity, larger pain areas, induced hyperalgesia around the infused knee, and reduced extension force. No significant pain facilitation or spreading of hyperalgesia was found after repeated infusions as compared with single infusions. Acidic saline infused into the infrapatellar fat pad provoked pain and localized mechanical hyperalgesia. Thus, this acid-induced pain model may mimic the early-stage responses to tissue injury of knee osteoarthritis.