Acupoint injection versus sacral canal injection in lumbar disc herniation: A protocol of randomized controlled trial.

BACKGROUND: Both acupoint injection and sacral canal injection are widely adopted in the treatment of lumbar disc herniation (LDH), but there are still doubts about the effectiveness and safety of the 2 methods. Therefore, the objective of the randomized controlled trial is to evaluate the effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH. METHOD: This is a prospective randomized controlled trial to study the effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH. With the approval by the clinical research ethics committee of our hospital, patients were randomly included into 1 of 2 treatment protocols:Patients, doctors, nurses, and research assistants responsible for collecting data were blinded to group allocation. Main outcome observation indicator: visual analogue scale; secondary outcome observation indicator: Oswestry disability index scores; paresthesia score; adverse reactions. Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL). DISCUSSION: The effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH were evaluated in this study, and the results of this trial would establish clinical evidence for the adoption of acupoint injection or sacral canal injection to treat LDH. TRIAL REGISTRATION NUMBER: DOI 10.17605 / OSF.IO / VTFUD.

Efficacy of Intradiscal Ozone Therapy with or without Periforaminal Steroid Injection on Lumbar Disc Herniation: A Double-Blinded Controlled Study.

BACKGROUND: Intradiscal ozone therapy, a minimally invasive technique, is used in patients that do not respond to standard conservative therapies for low back pain due to degenerative disc-induced lumbar disc herniation (LDH). Many studies on clinical efficacy lack a standardized injection method and are limited by inadequate study design. OBJECTIVE: This study aimed to determine the efficacy of periforaminal steroid injection together with intradiscal ozone therapy. STUDY DESIGN: A prospective, double-blinded, randomized controlled trial. SETTING: A tertiary care center. METHODS: This study was conducted in 65 patients with low back and leg pain caused by LDH. Group 1 received intradiscal ozone therapy (n = 35) and Group 2 received intradiscal ozone therapy with periforaminal steroid injection (n = 30). Patients were evaluated for pain using the visual analogue scale (VAS), for disability using Oswestry Disability Index (ODI), and for quality of life using the short form 36 health survey administered pre-injection and at one and 6 months post-injection. All procedures were performed under sterile conditions using C-arm fluoroscopy. RESULTS: Significant improvements were observed in pain, disability, and quality of life in both groups post-treatment compared to pre-injection. Mean pre-injection VAS was not significantly different between the groups (VAS: 7.8 ± 1.1 for Group 1, 7.8 ± 1.2 for Group 2). VAS values at 6 months for Group 1 and Group 2 were as follows: 3.6 ± 2.4, 4.1 ± 1.6, respectively) (P < 0.001). Mean pre-injection ODI was not significantly different between the groups (ODI: 20.9 ± 9.6 for Group 1, 25.2 ± 10.3 for Group 2). ODI values at 6 months for Group 1 and Group 2 were as follows: 12.8 ± 9.2, 14.3 ± 7.2, respectively) (P < 0.001). However, there were no significant differences between the groups. Similarly, there was no significant difference between the 2 groups on any of these parameters. LIMITATIONS: A limited number of patients and limited follow-up time. CONCLUSION: This study showed that intradiscal ozone injection alone was sufficient to treat low back and leg pain caused by LDH and that periforaminal steroid injection does not provide additional benefit, which is contrary to the literature.

Intrathecal versus local infiltration analgesia for pain control in total joint arthroplasty.

BACKGROUND: The purpose of this meta-analysis was to assess the efficacy of intrathecal morphine (ITM) analgesia and local infiltration analgesia (LIA) for pain control in total joint arthroplasty (TJA). METHODS: Embase, PubMed, the Cochrane Library, and Web of Science were systematically searched for randomized controlled trials (RCTs). All RCTs were comparing intrathecal analgesia and local infiltration analgesia in TJA. Primary outcomes were the visual analog scale (VAS) score with rest or mobilization up to 72 h. Secondary outcomes were the total morphine consumption, length of hospital stay, and morphine-related complications. RESULTS: Compared with the intrathecal analgesia group, the LIA group was associated with a reduction in VAS score with rest up to 72 h. Moreover, LIA was associated with a decrease in VAS score with mobilization at 6 h, 12 h, 48 h, and 72 h. Moreover, LIA significantly reduced total morphine consumption (weighted mean difference (WMD)  = - 15.37, 95% CI - 22.64 to - 8.83, P  = 0.000), length of hospital stay (WMD  =  - 1.39, 95% CI - 1.67 to - 1.11, P  = 0.000), and morphine-related complications (nausea and pruritus). CONCLUSIONS: Local infiltration provided superior analgesia and morphine-sparing effects within the first 72 h compared with ITM following TJA.

CT-guided drug injection around the nerve root to treat lumbar disc herniation.

To observe and analyze the effect of CT-guided drug injection around the nerve root in the treatment of lumbar disc herniation, the 140 patients diagnosed with lumbar disc herniation in our hospital, were selected as the study subjects for CT-guided drug injection around the nerve root and treatment efficacy was observed. According to the modified Mac Nab criteria, there were 80 cases, 50 cases, 6 cases, and 4 cases of excellent, good, fair, and poor results, with excellent and good rate at 92.86%; the patients whose onset time was less than three months and more than three months were compared in terms of VAS scores before and after surgery. The results showed that the postoperative pain score was significantly lower in patients whose onset time was less than three months compared to those whose onset time was more than three months, P<0.05; observation of patients' quality of life before and after treatment shows great improvement in quality of life after treatment, P<0.05. The treatment of lumbar disc herniation with CT-guided drug injection around the nerve root can achieve relatively good results with significantly improved therapeutic effect and great application value.

Nerve root injection cancellations because of incomplete anticoagulation management.

BACKGROUND: Computed tomography-guided steroid injection is a well-recognized, conservative treatment of localized spinal pain as a result of facet arthropathy and radiculopathy secondary to nerve root compression. An extremely rare complication is the development of an epidural haematoma with potential to cause permanent neurological damage, so anticoagulation at the time of procedure is contraindicated. Routinely injections are performed as an outpatient requiring the referring physician to implement a peri-procedural anticoagulation plan. Anecdotal experience suggested that cancellations were occurring as patients remained on anticoagulation at the time of their appointment. The authors therefore assessed the existing service against expected standards to identify the causes of cancellations and find ways to improve the service. AIMS: This audit aimed to identify the incidence of cancelled computed tomography-guided nerve root injections secondary to incorrect peri-procedural anticoagulation management, develop an intervention to help reduce the incidence of cancellations and then re-audit to assess the effect of the intervention. METHODS: The audit standard was that 100% of outpatients attending for computed tomography-guided nerve root and facet injections should have an appropriate anticoagulation plan implemented. Baseline data collection took place prospectively between 1 September and 30 November 2016. The study population was elective computed tomography-guided spinal nerve root and facet injections scheduled on the radiology information system at the authors' trust. Descriptive analysis was completed. The intervention involved a revised electronic request form being implemented with new compulsory fields concerning antiplatelets and anticoagulants. Re-audit post-intervention involved prospective data collection between 1 September and 30 November 2017 using the same methods. RESULTS: Baseline audit found that of three out of 55 (5%) patients had cancellations. On re-audit, there were 0 cancellations out of 93 patients. CONCLUSIONS: The new request form prevented 5% of patients referred for computed tomography-guided nerve root injection being cancelled because of incorrect anticoagulation management. Extrapolated over the year the potential savings through preventing lost activity are £3445.56.

Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Efficacy of intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B for post-neurosurgical intracranial infections due to MDR/XDR Acinectobacter baumannii: a retrospective cohort study.

Background: Post-neurosurgical intracranial infections caused by multidrug-resistant or extensively drug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality. In this study, we analyzed the therapeutic efficacy of intravenous combined with intrathecal/intracerebral ventricle injection of polymyxin B for this type of intracranial infection. Methods: This retrospective study was conducted from January 2013 to September 2017 at the Second Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou,China) and included 61 cases for which cerebrospinal fluid (CSF) cultures were positive for multidrug-resistant or extensively drug-resistant A. baumannii after a neurosurgical operation. Patients treated with intravenous and intrathecal/intracerebral ventricle injection of polymyxin B were assigned to the intrathecal/intracerebral group, and patients treated with other antibiotics without intrathecal/intracerebral injection were assigned to the intravenous group. Data for general information, treatment history, and the results of routine tests and biochemistry indicators in CSF, clinical efficiency, microbiological clearance rate, and the 28-day mortality were collected and analyzed. Results: The rate of multidrug-resistant or extensively drug-resistant A. baumannii infection among patients who experienced an intracranial infection after a neurosurgical operation was 33.64% in our hospital. The isolated A. baumannii were resistant to various antibiotics, and most seriously to carbapenems (100.00% resistance rate to imipenem and meropenem), cephalosporins (resistance rates of 98.38% to cefazolin, 100.00% to ceftazidime, 100.00% to cefatriaxone, and 98.39% to cefepime). However, the isolated A. baumannii were completely sensitive to polymyxin B (sensitivity rate of 100.00%), followed by tigecycline (60.66%) and amikacin (49.18%). No significant differences in basic clinical data were observed between the two groups. Compared with the intravenous group, the intrathecal/intracerebral group had a significantly lower 28-day mortality (55.26% vs. 8.70%, P = 0.01) and higher rates of clinical efficacy and microbiological clearance (95.65% vs. 23.68%, P < 0.001; 91.30% vs. 18.42%, P < 0.001, respectively). Conclusions: Intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B is an effective regimen for treating intracranial infections caused by multidrug-resistant or extensively drug-resistant A. baumannii.

Near Death Experience from Placement of an Intrathecal Catheter.

UNLABELLED: The management of pain due to cancer is challenging and often requires invasive therapy in addition to medication management. Intrathecal drug delivery is a form of advanced therapy that delivers medication locally in the intrathecal space while reducing systemic side effects associated with high doses of opioids. Although risks associated with intrathecal drug delivery are low, some common complications include dislodgement, kinking, or fracture of the catheter, bleeding, neurological injury, infection, and cerebrospinal leaks. We present a case of a 38-year-old woman with a medical history significant for stage IV breast cancer, L2 metastatic lesion, opioid tolerance, and chronic neck and low back pain who was admitted to the hospital for intractable pain. She had failed multiple interventional procedures in the past including lumbar medial nerve radiofrequency ablation, epidural steroid injection, and trigger point injections as well as a kyphoplasty at the L2 level. Failing both oral and parenteral opioid treatments, the decision was made to place an intrathecal pump in the patient. After placement of the intrathecal catheter and prior to any bolus of medication being given, the patient became bradycardic with a heart rate in the 20s and experienced a 10 second pause. The patient had intermittent bradycardia over the following days and symptoms resolved only after removal of the intrathecal catheter itself. To our knowledge, this is the first reported case with a complication of recurrent bradycardic and asystolic episodes prior to the administration of intrathecal opioid but shortly after placement of the intrathecal catheter itself. KEY WORDS: Intrathecal drug delivery, complications, cancer pain, intrathecal analgesia, bradycardia, opioids.

Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade.

[Neurosurgical treatment of chronic pain]. / Traitement neurochirurgical de la douleur chronique.

Neurosurgical treatment of pain is based on 3 concepts: 1) lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (cordotomy, radicotomy...), they are indicated to treat morphine-resistant cancer pain; 2) neuromodulation techniques try to decrease pain by reinforcing inhibitory mechanisms, using chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation...) to treat chronic neuropathic pain; 3) intrathecal infusion of analgesics (morphine, ziconotide), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, patients with severe and chronic pain, refractory to all other treatments.

Itch and analgesia resulting from intrathecal application of morphine: contrasting effects on different populations of trigeminothalamic tract neurons.

Intrathecal application of morphine is among the most powerful methods used to treat severe chronic pain. However, this approach commonly produces itch sufficiently severe that patients are forced to choose between relief of pain or itch. The neuronal populations responsible for processing and transmitting information underlying itch caused by intrathecal application of morphine have not been identified and characterized. We describe two populations of antidromically identified trigeminothalamic tract (VTT) neurons in anesthetized rats that are differentially affected by morphine and explain several aspects of opioid-induced itch and analgesia. We found that intrathecal application of morphine increased ongoing activity of itch-responsive VTT neurons. In addition, intrathecal application of morphine increased responses to pruritogens injected into the skin and greatly heightened responses to innocuous mechanical stimuli. In contrast, the ongoing activity and responses to noxious pinches in nociceptive VTT neurons were frequently inhibited by the same dose of morphine. These results reveal that i.t. application of morphine affects specific subpopulations of VTT neurons in ways that may produce itch, hyperknesis, alloknesis, and analgesia.

Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats.

Stroke is the dominant cause of sensorimotor disability that primarily affects the elderly. We now show that neuroplasticity and functional recovery after stroke is constrained by inhibitory chondroitin sulphates. In two blinded, randomized preclinical trials, degradation of chondroitin sulphate using chondroitinase ABC reactivated neuroplasticity and promoted sensorimotor recovery after stroke in elderly rats. Three days after stroke, chondroitinase ABC was microinjected into the cervical spinal cord to induce localized plasticity of forelimb sensorimotor spinal circuitry. Chondroitinase ABC effectively removed chondroitin sulphate from the extracellular matrix and perineuronal nets. Three different tests of sensorimotor function showed that chondroitinase ABC promoted recovery of forelimb function. Anterograde and retrograde tracing showed that chondroitinase ABC also induced sprouting of the contralesional corticospinal tract in the aged treated hemicord. Chondroitinase ABC did not neuroprotect the peri-infarct region. We show for the first time delayed chondroitinase ABC treatment promotes neuroanatomical and functional recovery after focal ischaemic stroke in an elderly nervous system.

Ozone therapy as a treatment for low back pain secondary to herniated disc: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Low back pain (LBP) is one of the most common and important health problems affecting the population worldwide and remains mostly unsolved. Ozone therapy has emerged as an additional treatment method. Questions persist concerning its clinical efficacy. OBJECTIVE: The purpose of our study was to evaluate the therapeutic results of percutaneous injection of ozone for low back pain secondary to disc herniation. STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials. METHODS: A comprehensive literature search was conducted using all electronic databases from 1966 through September 2011. The quality of individual articles was assessed based on the modified Cochrane review criteria for randomized trials and criteria from the Agency for Healthcare Research and Quality. OUTCOME PARAMETERS: The outcome measure was short-term pain relief of at least 6 months or long-term pain relief of more than 6 months. RESULTS: Eight observational studies were included in the systematic review and 4 randomized trials in the meta-analysis. The indicated level of evidence for long-term pain relief was II-3 for ozone therapy applied intradiscally and II-1 for ozone therapy applied paravertebrally. The grading of recommendation was 1C for intradiscal ozone therapy and 1B for paravertebral ozone therapy. LIMITATIONS: The main limitations of this review are the lack of precise diagnosis and the frequent use of mixed therapeutic agents. The meta-analysis included mainly active-control trials. No placebo-controlled trial was found. CONCLUSIONS: Ozone therapy appears to yield positive results and low morbidity rates when applied percutaneously for the treatment of chronic low back pain.

Comparison of intrathecal cilostazol and nimodipine treatments in subarachnoid hemorrhage: an experimental study in rabbits.

OBJECTIVE: intrathecal administration of calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Also, delayed CVS treatment model with oral administration of cilostazol can be seen in the literature. METHODS: in this study, 25 male New Zealand white rabbits were randomly assigned to five groups: control, SAH only, SAH/nimodipine, SAH/cilostazol, SAH/vehicle. The animals' basilar arteries were sectioned from four separate zones and four sections were obtained from each rabbit. Basilar artery luminal section areas were measured by using SPOT for windows Version 4.1 computer program. RESULTS: basilar artery luminal section areas in SAH/ nimodipine and SAH/ cilostazol groups were significantly higher than SAH only group (P < 0.05). CONCLUSION: phosphodiesterase 3 inhibitor cilostazol has vasodilatory effects without affecting cerebral blood flow. Nimodipine is a calcium channel blocker and is still used in vasospasm therapy either oral or intravenously. This study demonstrates that prophylactic bolus intrathecal administration of either cilostazol or nimodipine equally prevents SAH-associated CVS in an animal model. We therefore propose that cilostazol is a candidate for clinical trials in the treatment of delayed vasospasm.

Comparison of intrathecal dotarizine and nimodipine treatments in cerebral vasospasm after subarachnoid hemorrhage: an experimental study in rabbits.

BACKGROUND: cerebral vasospasm (CVS) is one of the most considerable complications of subarachnoid hemorrhage (SAH). The aim of this study was to assess and to compare the ability of intrathecal dotarizine and nimodipine to prevent and treat vasospasm in a rabbit model of subarachnoid hemorrhage. METHOD: thirty male New Zealand white rabbits weighing 2,500-3,000 g were allocated into five groups randomly. The treatment groups were as follows: Control, only SAH, SAH/Dotarizine, SAH/Nimodipine, SAH/Vehicle. Forty-eight hours after SAH injection, all animals underwent femoral artery catheterization procedure by open surgery under anesthesia and angiography performed for each animal in the fifth day just before sacrifice. FINDINGS: basilar artery vessel diameters are measured by angiography. Basilar artery vessel diameters and luminal sectional areas are measured in pathology slides. There was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (p < 0.05). CONCLUSIONS: these findings demonstrate that calcium channel blocker dotarizine has marked vasodilatory effect in an experimental model of SAH in rabbits. Nimodipine is an effect-proven agent in CVS, but dotarizine may take place of it.

Comparison of intrathecal flunarizine and nimodipine treatments in cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits.

BACKGROUND: the aim of this study was to assess and to compare the ability of intrathecal flunarizine and nimodipine to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHOD: forty male New Zealand white rabbits were allocated into 5 groups randomly. The treatment groups were as follows: (1) control (no SAH [n = 8]), (2) SAH only (n = 8), (3) SAH plus vehicle (n = 8), (4) SAH plus nimodipine (n = 8), and (5) SAH plus flunarizine (n = 8). Before sacrifice, all animals underwent femoral artery catheterization procedure by open surgery under anesthesia and angiography performed for each animal. FINDINGS: there was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (p < 0.05). Basilar artery vessel diameter and luminal section areas in group 4 were significantly higher than in group 2 (p < 0.05). Basilar artery vessel diameter and basilar artery luminal section areas in group 5 were significantly higher than in group 2 (p < 0.05).Basilar artery vessel diameter and basilar artery luminal section areas in group 5 were significantly higher than in group 4 (p < 0.05). CONCLUSIONS: these findings demonstrate that flunarizine has marked vasodilatatory effect in an experimental model of SAH in rabbits.

The effects of intrathecal nicergoline and nimodipine in cerebral vasospasm: an experimental study in rabbits.

BACKGROUND: the aim of this study was to assess and to compare the ability of intrathecal nicergoline and nimodipine in prevention of cerebral vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHOD: twenty male New Zealand white rabbits were allocated into four groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) control [no SAH (n = 5)], (2) SAH only (n = 5), (3) SAH plus nimodipine (n = 5), and (4) SAH plus nicergoline (n = 5). FINDINGS: there was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (p < 0.05). Basilar artery vessel diameter and luminal section areas in group 3 were significantly higher than in group 2 (p < 0.05). Basilar artery vessel diameter and basilar artery luminal section areas in group 4 were significantly higher than in group 2 (p < 0.05). There was no significant difference between basilar artery vessel diameter and basilar artery luminal section areas in group 3 and group 4. CONCLUSIONS: these findings demonstrate that intrathecal nicergoline has a vasodilatatory effect in an experimental model of SAH in rabbits but not more than that of nimodipine.

Mechanism of action of oxygen ozone therapy in the treatment of disc herniation and low back pain.

In the low back syndrome the pain has a multifactorial origin and ozone can surprisingly display a number of beneficial effects ranging from the inhibition of inflammation, correction of ischemia and venous stasis, and finally inducing a reflex therapy effect by stimulating anti-nociceptor analgesic mechanisms. The intradiscal and intramuscular injection of oxygen-ozone is a successful approach comparable to other minimally invasive procedures, but the elucidation of the mechanisms of action remains elusive. This communication shortly reports the mechanisms of action of oxygen ozone therapy at the level of intervertebral disc and paravertebral muscles.

Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112.

Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1-10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4-5h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.

Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids.

Both cyclooxygenase-1 and -2 are expressed in the spinal cord, and the spinal COX product prostaglandin E(2) (PGE(2)) contributes to the generation of central sensitization upon peripheral inflammation. Vice versa spinal COX inhibition is considered an important mechanism of antihyperalgesic pain treatment. Recently, however, COX-2 was shown to be also involved in the metabolism of endocannabinoids. Because endocannabinoids can have analgesic actions it is conceivable that inhibition of spinal COX produces analgesia not only by inhibition of PG synthesis but also by inhibition of endocannabinoid breakdown. In the present study, we recorded from spinal cord neurons with input from the inflamed knee joint and we measured the spinal release of PGE(2) and the endocannabinoid 2-arachidonoyl glycerol (2-AG) in vivo, using the same stimulation procedures. COX inhibitors were applied spinally. Selective COX-1, selective COX-2 and non-selective COX inhibitors attenuated the generation of spinal hyperexcitability when applied before and during development of inflammation but, when inflammation and spinal hyperexcitability were established, only selective COX-2 inhibitors reversed spinal hyperexcitability. During established inflammation all COX inhibitors reduced release of spinal PGE(2) almost equally but only the COX-2 inhibitor prevented breakdown of 2-AG. The reversal of spinal hyperexcitability by COX-2 inhibitors was prevented or partially reversed by AM-251, an antagonist at the cannabinoid-1 receptor. We conclude that inhibition of spinal COX-2 not only reduces PG production but also endocannabinoid breakdown and provide evidence that reversal of inflammation-evoked spinal hyperexcitability by COX-2 inhibitors is more related to endocannabinoidergic mechanisms than to inhibition of spinal PG synthesis.