Antineuropathic Drugs Research Articles

Finding predictors for successful opioid response in cancer patients: An analysis of data from four randomized controlled trials.

There is no consensus on which "strong" (or step 3 WHO analgesic ladder) opioid to prescribe to a particular patient with cancer-related pain. A better understanding of opioid and patient characteristics on treatment response will contribute to a more personalized opioid treatment. Assessment of potential predictors for successful opioid treatment response in patients with cancer pain. An international partnership between four cancer pain research groups resulted in a combined individual-level database from four relevant randomized controlled trials (RCTs; n = 881). Together, these RCTs investigated the short-term (1 week) and medium-term (4 or 5 weeks) treatment responses for morphine, buprenorphine, methadone, oxycodone, and fentanyl. Candidate predictors for treatment response were sex, age, pain type, pain duration, depression, anxiety, Karnofsky performance score, opioid type, and use of anti-neuropathic drug. Opioid type and pain type were found statistically significant predictors of short-term treatment success. Sex, age, pain type, anxiety, and opioid type were statistically, significantly associated with medium-term treatment success. However, these models showed low discriminative power. Fentanyl and methadone, and mixed pain were found to be statistically significant predictors of treatment success in patients with cancer-related pain. With the predictors currently assessed our data did not allow for the creation of a clinical prediction model with good discriminative power. Additional - unrevealed - predictors are necessary to develop a future prediction model.

Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain

Neuropathic pain remains a clinical challenge due to its complex and not yet fully understood pathomechanism, which result in limited analgesic effectiveness of the management offered, particularly for patients with acute, refractory neuropathic pain states. In addition to the introduction of several modern therapeutic approaches, such as neuromodulation or novel anti-neuropathic drugs, significant efforts have been made in the repurposing of well-known substances such as phenytoin. Although its main mechanism of action occurs at sodium channels in excitable and non-excitable cells and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level and how it influences morphine-induced analgesia have not been clarified, both being crucial from a clinical perspective. We demonstrated that single and repeated systemic administrations of phenytoin decreased tactile and thermal hypersensitivity in an animal model of neuropathic pain. Importantly, we observed an increase in the antinociceptive effect on thermal stimuli with repeated administrations of phenytoin. This is the first study to report that phenytoin improves morphine-induced antinociceptive effects and influences microglia/macrophage activity at the spinal cord and dorsal root ganglion levels in a neuropathic pain model. Our findings support the hypothesis that phenytoin may represent an effective strategy for neuropathic pain management in clinical practice, particularly when combination with opioids is needed.

Paracetamol for multimodal analgesia.

Pain and related disability remain a major social and therapeutic problem. Comorbidities and therapies increase drug interactions and side effects making pain management more compounded especially in the elderly who are the fastest-growing pain population. Multimodal analgesia consists of using two or more drugs and/or techniques that target different sites of pain, increasing the level of analgesia and decreasing adverse events from treatment. Paracetamol enhances multimodal analgesia in experimental and clinical pain states. Strong preclinical evidence supports that paracetamol has additive and synergistic interactions with anti-inflammatory, opioid and anti-neuropathic drugs in rodent models of nociceptive and neuropathic pain. Clinical studies in young and adult elderly patients confirm the utility of paracetamol in multimodal, non-opioid or opioid-sparing, therapies for the treatment of acute and chronic pain.

Erythromelalgia: Definition, clinical contexts, differential diagnosis, and therapy. Single case and literature update

Clinical publications on this morbid condition report as many as 16 different Nav1 7 channel substitutions. They also report more than 40 pharmacological treatments, including agents with sodium channel blocking but nonspecific activity (mexiletine, lidocaine, carbamazepine), anti-neuropathic drugs (gabapentinoids and antidepressants), antidepressant drugs with efficacy on migraines (amitriptyline) vasoactive drugs for the management of hypertension, and analgesics (opioids and ketamine). Current research fails to address all patients’ clinical needs, although it recently suggests new genetic hypotheses yet to be tested and the central importance of genetic counseling, to inform patients and their families about the severity, likely course of symptoms, and risk of complications, and in some cases to guide clinical management. Current findings and the significant morbidity associated with the condition, even in light of the single case presented, highlight the need for mechanism-based therapies to improve clinical outcomes.

Gelsemium effect against nerve injury-induced mechanical allodynia and hyperalgesia

Background Gelsemium dilutions are prescribed for their anxiolytic and its analgesic effects. Investigations using alkaloids isolated from Gelsemium support the hypothesis of Gelsemium-induced analgesia. Aims We evaluated the antinociceptive effect of Gelsemium dilutions 3, 5 and 9C in neuropathic models. Methodology To investigate the potential effect of Gelsemium dilutions 3, 5 and 9C to prevent or to correct sciatic nerve chronic constriction (CCI) injury, we used the von-Frey hair behavioral test. CCI-induced neuropathic pain in rats represents characteristic painful behaviors like hyperalgesia and allodynia, thus validating its suitability for the evaluation of anti-neuropathic drugs. To test the corrective effect, Gelsemium 3, 5 or 9 C or placebo were administered from Day 14 after sciatic nerve ligation, i.e., when neuropathic symptoms were observed. In the preventive strategy, Gelsemium dilutions and placebo began immediately after the sciatic nerve ligation (D0). Results and discussion We observed that in placebo groups, the mechanical-sensitivity thresholds remained unchanged all treatment days whereas Gelsemium dilutions 3C and 5C exerted a strong or moderate antinociceptive effect, respectively. In CCI-rats, the contralateral paw of placebo-treated animals did not respond to 4g non-noxious stimulation but the ipsilateral responses increased progressively (0%-D0, 52%-D14, 72%-D21 and 88%-D28), confirming the occurrence of allodynia. Gelsemium dilution 3C corrective and preventive treatments efficiently reduced the allodynic responses (72-to-38%-D21 and 88-to-22%-D28). Gelsemium 5C also exhibited significant anti-allodynic action while Gelsemium 9C was ineffective. Similarly, one week treatment with Gelsemium 3 or 5C efficiently reduced 15g or 26g-evoked hyperalgesia and the beneficial action improved after 2 weeks. Chronic therapies with current analgesics induce several side-effects. Conclusion The present work, suggest that Gelsemium dilutions devoid of toxicity and used as anxiolytic in humans induced analgesia, opens interesting/alternative perspectives for long-term management of pain without undesirable effects.

Chemotherapy-induced peripheral neuropathy (CIPN)

Many cancer patients are cured from their malignant tumor, but may suffer from long-term, chemotherapy-induced peripheral neuropathy. This frequent and often disabling condition results from treatment with anticancer drugs including microtubulin-targeting agents such as taxanes, vinca alkaloids, and some immunotoxins; platinum compounds; certain proteasome inhibitors like bortezomib; and immunomodulatory drugs such as thalidomide. Moreover, immune checkpoint inhibitors can cause an autoimmune-mediated peripheral neuropathy. Neuropathic symptoms include pain, numbness, tingling, or cold hypersensitivity in the hands and feet, as well as motor weakening or disorders of the autonomous nerve system. Medical treatment is often unsatisfactory. First-line options include antidepressants like duloxetine, venlafaxine or amitriptyline, and antineuropathic drugs like gabapentin or pregabalin. In addition, topical therapies with capsaicin or lidocaine have been applied. In severe cases, medication with tramadol or opioids may be required for painful paresthesia. Physiotherapy, sensory integrative occupational therapy, and various physical agents can be helpful. The course of disease, however, is usually protracted, and the symptoms generally gradually decrease. In this short overview, we describe medical and physical treatment options for chemotherapy-induced peripheral neuropathy.

Efficacy of different interventions for the treatment of postherpetic neuralgia: a Bayesian network meta-analysis

ObjectiveWe aimed to perform a network meta-analysis that combined both direct and indirect evidence to compare the relative efficacy of interventional therapies to treat patients with postherpetic neuralgia (PHN) and to determine the treatments’ superiority and validity.MethodA conventional paired meta-analysis was performed. This was followed by a network meta-analysis using the Bayesian framework.ResultsBotulinum toxin type A and pulsed radiofrequency (PRF) were the two most effective individual interventions. For combination therapy, PRF + nerve block (NB) was the best choice, followed by subcutaneous injection or local infiltration (SC) + NB + ozone (O3). However, the combination of PRF + NB + SC showed reduced the efficacy compared with each treatment and was highly invasive for patients. After a long-term follow-up, PRF was shown to be the most effective therapy for treating patients with PHN.ConclusionsRegular anti-neuropathic drug administration that was accompanied by interventional therapies at an early stage is the best choice to treat patients with PHN. Appropriate combinations of different interventions show improved pain relief. Clinicians should manage therapeutic regimens on the basis of the patients specific condition and existing measures and strive to achieve personalized treatment.

Management of chronic abdominal wall pain: A one-year

Objectives: This study was designed to determine the prevalence of chronic abdominal wall pain (CAWP) in the gastroenterology clinic unit (GCU) and investigated the criteria of CAWP patients. Therapeutic trials to control such annoying problem were investigated. Methods: The study had two stages; the first stage was a cross-sectional analysis of the adult patients who were suffering from chronic abdominal pain. Patients reporting a score value ≥ 10 on the Questionnaire of CAWP in addition to a positive Carnett´s sign were included in this study. Included patients were subjected to study the criteria of CAWP. The second stage was a randomized clinical trial where anti-neuropathic drugs (e.g. pregabalin-carbamazepine-amitriptyline) were used. Results: CAWP was diagnosed in 30.6% of the screened patients. 76% were female. Upper right quadrant pain was reported in 48.1%. Delay in diagnosis was reported to be 9.14±8.9 months. Misdiagnosis as cholecystitis, peptic ulcer disease and irritable bowel syndrome was reported. 94.4 % of treated patients showed a satisfactory response to anti-neuropathic medications. 5.6 % was successfully controlled by local injection. Significant lower Visual Analogue Scale (VAS) was reported after 2 weeks and 1, 2, 3, 4 and 6 months of the treatment plan implementation when comp-ared to the basal value (p. < 0.001). Conclusions: CAWP was identified in 30.6% of the patients complaining of chronic abdominal pain. Multiple physician consultations, delayed diagnosis, mis-diagnosis with subsequent mistreatment were common. While, anti-neuropathic drugs are an effective tool in most cases of CAWP, trigger point injection represents an alternative line of treatment.

Radiofrequency Thoracic Sympathectomy for Sympathetically Maintained Chronic Post-Mastectomy Pain, a Preliminary Report: 6-Month Results.

Evaluation of the analgesic efficacy of radiofrequency thoracic sympathectomy for sympathetically maintained post-mastectomy pain syndrome (PMPS). Patients with PMPS randomized to Group TS (n=33) received radiofrequency thoracic sympathectomy, and those randomized to Group Sham (n=33) received no radiofrequency current. Postoperative pain treatment consisted of duloxetine, pregabalin, and tramadol for both groups. The outcome variables were the proportion of patients who showed >50% reduction in their VAS pain score, the pain intensity measured by VAS score, and the global perceived effect (GPE) evaluated during the 6-month follow-up period. A significantly higher proportion of patients experienced >50% reduction in pain in Group TS (Group TS 25/30 [83.3%] vs. Group Sham 18/31 [58%], P=0.032); the proportion of patients who experienced >50% reduction in their pain without analgesics was significantly higher in Group TS (Group TS 10/25 [40%] vs. Group Sham 0/18 [0%], P=0.001). Furthermore, the proportion of patients treated with tramadol+duloxetine+pregabalin who experienced >50% reduction in their pain was significantly lower in Group TS (Group TS 0/25 [0%] vs. Group Sham 13/18 [75%], P=0.001). The VAS pain score was significantly lower in Group TS at 2weeks and at 1, 2, 3, and 6 months following the procedure. The GPE was significantly higher in Group TS (Group TS median GPE [interquartile range]) 7 [5, 7] vs. Group Sham median GPE [interquartile range]) 5 [4, 6]) P<0.001). Radiofrequency thoracic sympathectomy for sympathetically maintained PMPS decreased VAS pain scores and reduced the need for anti-neuropathic drugs, particularly opioid medications, and provided better patient satisfaction.

Evaluation of clinical outcomes in neuropathic pain with combinations of anti-neuropathic drugs

Background: Much of the pharmacological treatment modalities especially individual drugs for treating neuropathic pain have unwanted side effects, multiple day to day dosing, modest efficacy of topical treatments, and their local side effects. Combination drug regimen has the advantage of offering relatively better pain relief at lower drug doses and lesser side effects.Methods: The study was conducted in the Department of Neurology at NRI General Hospital, Guntur. The patients who met the inclusion and exclusion criteria were enrolled and assigned into 3 groups of the study drug combinations. The baseline characteristics and post interventional scores of Toronto Clinical Scoring System (TCSS), visual analogue scale (VAS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Medical outcome of sleep scale (MOS) and were analyzed using t test and mean difference.Results: A statistically significant reduction in neuropathic pain in all the three groups was found. The mean difference between the baseline and post interventional scores of TCSS and VAS of group I, II and III were 2.97, 2.75, and 1.97; 2.32, 1.12, and 0.95 respectively. There was a statistically significant improvement of HAM-A in all the three groups, HAM-D and MOS sleep scale were found significant only in group II.Conclusions: The study findings revealed that all the three drug combinations were effective in the management of neuropathic pain with pregabalin and oxcarbazepine combination being better with respect to efficacy and tolerability. Regarding the treatment of depression and sleep disturbances associated with NP pregabalin and duloxetine was more effective.

Benefits of using the Brief Pain Inventory in patients with cancer pain: an intervention study conducted in Swedish hospitals

PurposeThe prevalence of cancer pain is too high. There is a need for improvement of pain management in cancer care. The aim of this study was to explore whether the use of the multidimensional pain assessment questionnaire Brief Pain Inventory (BPI) could improve pain relief in hospitalized patients with cancer.MethodsA controlled intervention study was performed at two hospitals in western Sweden, 264 patients were included, 132 formed a control group and 132 an intervention group. All participants completed the BPI and the Edmonton Symptom Assessment Scale (ESAS) at baseline. Only the researcher had access to questionnaires from the control group. The completed forms from the intervention group were presented to the patients’ care team. A follow-up took place after 2–5 days when patients in both groups rated the scales a second time.ResultsIn the intervention group, significant differences in all measured items of the BPI were found at follow-up compared with baseline. Symptoms rated with the ESAS also decreased significantly, except shortness of breath. At follow-up, a significant increase in regular use of paracetamol, anti-neuropathic pain drugs and opioids was found, as well as elevated doses of fixed-schedule opioids. In the control group, differences between baseline and follow-up were significant regarding average pain and worst pain over the past 24 h.ConclusionPresenting the patient-reported BPI to the care team helped them to focus on patients’ pain, identify pain mechanisms and adjust analgesics accordingly. A possible explanation for the results is changes in the medication prescribed.

Nociceptive mechanisms involved in the acute and chronic phases of a complex regional pain syndrome type 1 model in mice

Complex regional pain syndrome I (CRPS-I) is a chronic painful pathology still undertreated. CTK 01512–2 is a recombinant version of the spider peptide Phα1β, and it functions as a voltage-gated calcium channel blocker and a transient receptor potential ankyrin 1 (TRPA1) antagonist with antinociceptive effect in different pain models. Here, we investigate the mechanisms involved in the acute and chronic nociceptive phases of a model of CPRS-I in mice and assess the antinociceptive effect of CTK 01512–2 using this model. Adult male and female mice C57BL/6 (20–30 g) were used to determine mechanical (von Frey test) or cold (acetone test) allodynia induction. Inflammatory parameters (serum and tibial nerve lactate levels, hind paw temperature and edema, or tissue cell infiltration) were evaluated after chronic post-ischemia pain (CPIP, a model of CPRS-I) induction. Anti-inflammatory and anti-neuropathic drugs or CTK 01512–2 were tested. First, we detected that CPIP-induced mechanical and cold allodynia in male and female mice in a similar way. In the acute phase (1 day after CPIP), an increase in inflammatory parameters were observed, as well as the anti-allodynic effect of anti-inflammatory compounds. In the chronic phase (17 days after CPIP), mice exhibited mechanical and cold allodynia, and anti-neuropathic drugs induced antinociception, while no inflammatory alterations were found. CTK 01512–2 reversed the CPIP allodynic effect in both nociceptive phases. Thus, this CPRS-I model can be used to understand the mechanisms involved in CPRS-I induced pain and inflammation. Besides, we observed that CTK 01512-2 has a valuable antinociceptive effect in this pain model.

Percutaneous balloon compression of Gasserian ganglion for idiopathic trigeminal neuralgia

Objective: The aim of this study was to evaluate the outcome and complication in patients with idiopathic trigeminal neuralgia (TN) posted for percutaneous balloon compression (PBC). Materials and Methods: The study included twenty patients of idiopathic TN presented in the outpatient department of pain clinic posted for PBC from the years 2016 to 2018. All patients were followed up for 6 months after the balloon compression of Gasserian ganglion. Out of the twenty patients, 40% were female and 60% were male. The mean age was 55.4 years (range: 37–70 years). These patients were on antineuropathic (carbamazepine, baclofen, and gabapentin) drugs with inadequate pain relief and 13 patients also had undergone radiofrequency ablation. PBC of Gasserian ganglion was planned by the technique described by Mullan and Lichtor in all patients. Visual Analog Score (VAS) and Barrow Neurological Intensity (BNI) score were compared pre and post procedure. Intraoperative and postoperative complications and side effects were analyzed retrospectively. Results: Eighteen out of twenty patients (90%) had excellent results with improvement in the VAS and BNI scores, which was statistically significant. The difference between the mean change in VAS and BNI scores for single nerve and multiple nerve roots was not statistically significant. Nearly 85% (17) of the patients had initial facial numbness, which improved in about 3 months. Only 10% of the patients had residual facial numbness, which was mild in nature and not bothersome to the patients. Masseter muscle weakness was present in seven (35%) patients. No patient reported corneal anesthesia or any other complications. Intraoperatively, four patients (20%) experienced moderate-to-severe bradycardia during entry to the foramen ovale and on inflation of the Fogarty balloon, which responded to injection atropine 0.6 mg intravenously stat. Conclusion: Hereby, we state that PBC is an effective and safe method with marked improvement in pain scores and improvement in quality of life of patients of idiopathic TN.

Analgesic Drug Prescription After Carpal Tunnel Surgery

Carpal tunnel syndrome is a frequent cause of neuropathic pain of the upper limb. Surgery is often proposed in second-line treatment, leading to an expected decrease in analgesic drug consumption. The main objective of this study was to investigate the variations in analgesic drug prescriptions, with a special focus on constant or increasing prescription patterns, before and after surgery for carpal tunnel syndrome. We designed a retrospective cohort study of French beneficiaries from the health insurance system in Midi-Pyrénées area. All patients undergoing carpel tunnel surgery during a specified period were identified and included. Definition of increased or constant prescription of analgesics was based on the comparison of the accumulated defined daily doses received by months and a difference between early preoperative (2 months before) and late postoperative period (2-12 months after surgery) superior to a -3.5 margin. We performed 4 multivariate logistic regression models to identify factors associated with increased or constant analgesic drug prescription patterns (for all analgesics, opioid, antineuropathic, nonopioid drugs). Among the 3665 patients included, 3255 (89%) received at least 1 analgesic drug during the late postoperative period (39% [n = 1426] for opioids and 15% [n = 563] for antineuropathic drugs). Prescription of analgesic, opioid, or antineuropathic drugs was maintained or increased in the late postoperative period in 11%, 5%, and 3% of the population, respectively. High levels of preoperative pain and female sex were associated with an increase in opioid use, whereas inpatient surgery (vs ambulatory surgery), high levels of preoperative pain, and psychiatric disorders were found to be associated with an increase in antineuropathic drug use. This study revealed that approximately 3% to 5% of patients undergoing carpal tunnel surgery had persistent and even increased use of opioid or antineuropathic drugs more than 2 months after surgery, in relation with possible chronic postoperative pain. Considering the incidence of carpal tunnel syndrome, the risks associated with persistent opioid use in this population should be further monitored.

Incidence of taxane-induced peripheral neuropathy receiving treatment and prescription patterns in patients with breast cancer.

Taxane-induced peripheral neuropathy (TIPN) can affect quality of life and treatment outcomes in breast cancer patients. Despite the high incidence, treatment of PN has not been established. This study aimed to evaluate the incidence, risk factors, and prescribing pattern of TIPN receiving pharmacologic treatment in real-world practice. We conducted a retrospective chart review of 1629 breast cancer patients who received taxanes at the Seoul National University Hospital from July 2012 to June 2014. We determined the incidence and predictors for TIPN treated with anti-neuropathic pain medications during taxane treatment and the 1-year follow-up period after discontinuation of taxanes. The prescribing pattern of anti-neuropathic drugs was also analyzed. A total of 1516 patients with breast cancer were included, and the incidence of TIPN receiving treatment was 21.9% overall, with 42.2% of patients using paclitaxel and 15.8% using docetaxel. The median time to the first anti-neuropathic pain medication prescribed from the start of taxane treatment was 64days and was significantly earlier in the paclitaxel group. In 21% of patients, TIPN treatment was started after the end of taxane treatment. Identified risk factors for TIPN were paclitaxel use (vs. docetaxel), old age, overweight, metastatic (vs. non-metastatic) breast cancer, and possibly a 3-weekly taxane schedule (vs. weekly). Gabapentin and pregabalin accounted for 71.7 and 24.3% of total use of anti-neuropathic agents, respectively. One-fifth of breast cancer patients who were treated with taxane-based chemotherapy experienced TIPN receiving treatment, and its risk factors were paclitaxel use, old age, overweight, and metastatic cancer.

Thomboprophylaxis In Multiple Myeloma Patients Treated With Lenalidomide or Thalidomide

August 2015 e65 of diabetes, rheumatoid arthritis and psychiatric disorders were associated with an increase in opioid use, whereas hospitalisation (versus ambulatory surgery), high level of preoperative pain and psychiatric disorders were found to be associated with an increase in antineuropathic drug use. Conclusions: This study revealed that around 1 out of 3 patients undergoing carpal tunnel surgery had persistent and even increased use of opioids and antineuropathics drugs more than two months after surgery, in relation with possible chronic postoperative pain. Considering the incidence of carpal tunnel syndrome, the risks associated with persistent opioid use in this population should be further monitored.

Complex regional pain syndrome.

Complex regional pain syndrome is an uncommon chronic pain condition. It develops spontaneously or following an injury. The features are limb pain, allodynia, hypersensitivity, hyperalgesia, abnormalities of the vasomotor, sudomotor and motor systems, and trophic changes, with reduced use of the affected limb. The diagnosis is clinical and one of exclusion. The emphasis of therapy is graded rehabilitation and movement of the limb with physiotherapy and occupational therapy. Psychological therapies should be offered if a patient is making no or slow progress in the acute phase, and to all patients in the chronic phase as depression can occur. The goal of pharmacotherapy is to assist functional improvement. The early phase may be managed with simple analgesia. Antineuropathic drugs including tricyclic antidepressants and antiepileptic drugs may be added. Other treatments with some evidence of effectiveness include corticosteroids, calcitonin and bisphosphonates. Vitamin C has been used for primary prevention after wrist fracture and upper and lower limb surgery. There is no evidence that it is effective for treating established complex regional pain syndrome.

N-methylthioacetylation of RYYRIK-NH2 with enhanced specific binding affinity and high antagonist activity for nociceptin ORL1 receptor

Antagonists of the neuropeptide nociceptin are expected to be potential analgesic and antineuropathic drugs acting on ORL1 GPCR receptors. The peptide library-based antagonist Ac-RYYRIK-NH2 inhibits the nociceptin activity mediated through ORL1, but preserves a considerably high level of agonist activity. We previously reported that the N-terminal acyl group is important for interaction with specific receptors, and developed isovarelyl-RYYRIK-NH2, which exhibits strong antagonist activity with negligible agonist activity. In the present study, in order to obtain a more potent antagonist, we further modified the isovarelyl group by replacing its Cβ atom with an oxygen, nitrogen, or sulfur atom to give the methyl group improved interaction ability. The methyl group bound to such heteroatoms was expected to enhance the hydrophobic interaction between the peptide and the ORL1 receptor. The RYYRIK-NH2 peptide with a methylthioacetyl group, CH3SCH2CO, revealed a higher receptor-binding affinity with strong antagonist activity, and the results suggested the presence of a receptor aromatic group as a complementary residue of this CH3S group.

Tritium-labelled isovaleryl-RYYRIK-NH2 as potential antagonist probe for ORL1 nociceptin receptor

IsoVa-RYYRIK-NH2 is a highly specific antagonist ligand of the opioid receptor-like 1 (ORL1) receptor, an endogenous ligand of which is 17-mer peptide nociceptin. ORL1 antagonists have potential for clinical use as analgesic and antineuropathic drugs, and thus information on the receptor-binding characteristics of antagonists is very important for rational drug design. In the present study, we prepared tritium-labelled isova-RYYRIK-NH2 from its precursor with the 3-methylcrotonyl (CH3)2CCHCO group by a catalytic reduction using tritium gas. The resulting [3H]isoVa-RYYRIK-NH2 was evaluated in a saturation binding assay using the COS-7 cell membrane preparations of transiently expressed ORL1. It exhibited more than 90% specific binding with a dissociation constant of 1.21±0.03nM. From the mutual heterologous binding assays using [3H]isoVa-RYYRIK-NH2 and [3H]nociceptin, isoVa-RYYRIK-NH2 and nociceptin were found to share the receptor-binding site, but each also had a separate specific binding site of its own. They differentiated the two different binding states or conformations of ORL1, which might represent the agonist-active and antagonist-inactive conformations of ORL1. [3H]isoVa-RYYRIK-NH2 is thus a key tracer to uncover the amino acid residues important for receptor inactivation.

Analgesic drug consumption increases after knee arthroplasty: A pharmacoepidemiological study investigating postoperative pain

Knee arthroplasty remains the gold standard in the treatment of severe osteoarthritis. Chronic postoperative pain has been reported with a prevalence ranging from 15% to 47%. The aim of this study was to compare analgesic drug consumption before and after surgery as an indicator of pain after knee surgery. A pharmacoepidemiological method comparing analgesics and antineuropathic issues 1year before and 1year after surgery was used. All patients who underwent knee arthroplasty in the Midi-Pyrenees region (2.5 million inhabitants) were identified through the Health Insurance System Database. Increase of drug issues (all analgesics, antineuropathic drugs, strong opioids) was calculated and compared between several periods surrounding the surgery (12months, 2months, and 10months before and after the knee arthroplasty). A multivariate logistic regression model was used to identify factors associated with chronic postoperative pain. The study included 1939 patients. An increase in analgesic, antineuropathic, and opioid drug consumption was observed the year after the surgery in 47.3%, 8.6%, and 5.6% of patients, respectively. Multivariate analysis found a significant association between type of surgery (total knee vs unicompartmental arthroplasty) and analgesic consumption 1year after surgery, and between preoperative pain and psychiatric vulnerability and increase in neuropathic drug dispensing. Conversely, older age was considered as a protective factor. This study revealed that an increase in the issue of different analgesic drugs is present in half of patients 1year after knee arthroplasty. Several associated factors of drug consumption (preoperative pain, type of surgery, and psychiatric disorder) were identified.