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Opioids have been and continue to be used for the treatment of chronic pain. Evidence supports the notion that opioids can be safely administered in patients with chronic pain without the development of addiction or chemical dependency. However, over the past several years, concerns have arisen with respect to administration of opioids for the treatment of chronic pain, particularly non-cancer pain. Many of these involve legal issues with respect to diversion and prescription opioid abuse. Amongst these, opioid induced hyperalgesia (OIH) is becoming more prevalent as the population receiving opioids for chronic pain increases. OIH is a recognized complication of opioid therapy. It is a pro-nocioceptive process which is related to, but different from, tolerance. This focused review will elaborate on the neurobiological mechanisms of OIH as well as summarize the pre-clinical and clinical studies supporting the existence of OIH. In particular, the role of the excitatory neurotransmitter, Nmethyl-D-aspartate appears to play a central, but not the only, role in OIH. Other mechanisms of OIH include the role of spinal dynorphins and descending facilitation from the rostral ventromedial medulla. The links between pain, tolerance, and OIH will be discussed with respect to their common neurobiology. Practical considerations for diagnosis and treatment for OIH will be discussed. It is crucial for the pain specialist to differentiate amongst clinically worsening pain, tolerance, and OIH since the treatment of these conditions differ. Tolerance is a necessary condition for OIH but the converse is not necessarily true. Office-based detoxification, reduction of opioid dose, opioid rotation, and the use of specific NMDA receptor antagonists are all viable treatment options for OIH. The role of sublingual buprenorphine appears to be an attractive, simple option for the treatment of OIH and is particularly advantageous for a busy interventional pain practice. Key words: Opioid hyperalgesia, hyperalgesia, tolerance, NMDA receptor antagonists, NMDA receptor induced hyperalgesia, spinal dynorphin induced hyperalgesia, descending facilitation and hyperalgesia, buprenorphine and hyperalgesia, opioid detoxification, officebased detoxification, complications of opioid therapy

Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Opioid-induced hyperalgesia (OIH) is a condition in which prolonged opioid use paradoxically increases sensitivity to noxious stimuli, resulting in heightened discomfort and diminished tolerance. This study aimed to investigate the clinical effects of Memantine in managing OIH symptoms in opioid-dependent patients. A randomized clinical trial involving 36 opioid-addicted patients diagnosed with opioid-induced hyperalgesia (OIH) was conducted between January and June 2022. Participants were randomly assigned to one of two groups: an intervention group receiving 10 mg/day of memantine, and a control group receiving placebo. The Cold Pressure Test (CPT) and Visual Analog Scale (VAS) were utilized to assess pain tolerance and intensity, respectively. The memantine group showed significantly increased cold pain tolerance at two and four weeks post-intervention ( p  = 0.005 and p  < 0.001) and a significant reduction in pain intensity at two week ( p  = 0.001), though not at four weeks ( p  = 0.4536). Repeated measures ANOVA indicated significant within-subject effects of time for both CPT (F = 41.694, p  = 0.001, η² = 0.558) and VAS (F = 69.065, p  = 0.001, η² = 0.677), while between-group and interaction effects were not significant. This study offers preliminary support for the potential efficacy of 10 mg/day memantine in alleviating OIH symptoms, warranting further investigation to confirm these findings. Trial registration IRCT registration number IRCT20211112053045N1. Registration date 07/12/2021. IRCT URL https//irct.behdasht.gov.ir/trial/60,058. Ethical code IR.ZUMS.REC.1400.26.

Recent evidence supports a functional connection between gut microbiota and the nervous system. Here the authors show that gut microbiota plays a critical role in the development of chemotherapy-induced pain. This role of the microbiota is likely mediated, in part, by Tlr4 expressed on hematopoietic cells, including macrophages. Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.

The aim of this investigation was to evaluate the effects of local anaesthesia on nerve growth factor (NGF) induced masseter hyperalgesia. Healthy participants randomly received an injection into the right masseter muscle of either isotonic saline (IS) given as a single injection (n = 15) or an injection of NGF (n = 30) followed by a second injection of lidocaine (NGF + lidocaine; n = 15) or IS (NGF + IS; n = 15) in the same muscle 48 h later. Mechanical sensitivity scores of the right and left masseter, referred sensations and jaw pain intensity and jaw function were assessed at baseline, 48 h after the first injection, 5 min after the second injection and 72 h after the first injection. NGF caused significant jaw pain evoked by chewing at 48 and 72 h after the first injection when compared to the IS group, but without significant differences between the NGF + lidocaine and NGF + IS groups. However, the mechanical sensitivity of the right masseter 5 min after the second injection in the NGF + lidocaine group was significantly lower than the second injection in the NGF + IS and was similar to the IS group. There were no significant differences for the referred sensations. Local anaesthetics may provide relevant information regarding the contribution of peripheral mechanisms in the maintenance of persistent musculoskeletal pain.

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.

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.

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that can occur after a cerebrovascular accident. This syndrome is characterised by pain and sensory abnormalities in the body parts that correspond to the brain territory that has been injured by the cerebrovascular lesion. The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability. The exact prevalence of CPSP is not known, partly owing to the difficulty in distinguishing this syndrome from other pain types that can occur after stroke (such as shoulder pain, painful spasticity, persistent headache, and other musculoskeletal pain conditions). Future prospective studies with clear diagnostic criteria are essential for the proper collection and processing of epidemiological data. Although treatment of CPSP is difficult, the most effective approaches are those that target the increased neuronal hyperexcitability.

Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.