Intermittent versus continuous esketamine infusions for long-term pain modulation in complex regional pain syndrome: protocol of a randomized controlled non-inferiority study (KetCRPS-2).

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. METHODS: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. DISCUSSION: If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05212571 , date of registration 01-28-2022. PROTOCOL VERSION: Version 3, February 2022.

Complex regional pain syndrome in a patient with neuroendocrine tumour under treatment with everolimus.

Everolimus is an immunosuppressant agent used in organ transplantation and, more recently, in cancer therapy. It has demonstrated beneficial effects in breast cancer, renal cancer, and neuroendocrine tumours. However, the treatment is not without side effects, some of which are still little known. We report the case of a 56 year-old man with a diagnosis of neuroendocrine tumour who developed a complex regional pain syndrome (CRPS) secondary to treatment with everolimus. CRPS has been linked to treatments with everolimus in renal and breast cancer patients as well as in renal transplant patients. To our knowledge, this is the first case of CRPS in a neuroendocrine tumour patient on everolimus treatment.

Recurrence of complex regional pain syndrome after administration of adenosine.

Background: The effects of adenosine in acute chronic pain are not clear. Literature supports both a pronociceptive/inflammatory role of the A2aR/A2bR and antihyperalgesia/allodynia with A1Rs/A3Rs. Adenosine could participate in the reactivation of chronic regional pain syndrome (CRPS) through inflammatory pathways and via A2Rs. Plastic changes in the brain CRPS-related overlap with those seen in systemic inflammation and persist even after symptoms of CRPS resolve. Aim: To illustrate the hypothesis that intravenous adenosine can reactivate dormant CRPS. Case report: An individual with successfully treated CRPS developed supraventricular tachycardia, he was treated with intravenous adenosine. Shortly after a second dose, he developed severe pain at a lower limb from relapsed CRPS. Treatment included lumbar sympathetic block, physical therapy and pharmacological agents. Conclusion: Intravenous adenosine can reactivate dormant CRPS. Its potential pronociceptive role in CRPS calls for further studies to better elucidate the underlying mechanisms.

Tacrolimus-Induced Pain Syndrome After Bone Marrow Transplantation: A Case Report and Literature Review.

BACKGROUND: Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with bone marrow transplants, is associated with the use of cyclosporine A (CsA) or tacrolimus (FK506). This case demonstrates the successful pain control of FK506-related CIPS in a 23-year-old male patient with previously reported characteristic clinical features of CIPS in addition to neuropathic symptoms and uncharacteristic imaging findings. On day 15 after the transplantation, the patient complained of severe pain in the lower limbs. Afterwards, the patient started to complain of pain on his hands and back too. During this period, FK506 levels ranged from 9.5 to 16.1 ng/mL. All laboratory exams were normal, except for an increased level of alkaline phosphatase (141 U/L). The pain was not ameliorated by various analgesic drugs. Although MRI done for our patient showed no typical radiological signs such as bone marrow edema, CIPS was suggested based on characteristic clinical features of CIPS. Of note, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with CIPS. CONCLUSION: The patient was treated successfully by switching FK506 to CsA and administrating gabapentin and nifedipine. Heightened awareness of this complication after bone marrow transplants may be needed for hematologists, otherwise CIPS can result in catastrophic consequences.

Síndrome posvacunal VPH. ¿Un espejismo clínico, o un nuevo modelo trágico de fibromialgia? / HPV vaccination syndrome: A clinical mirage, or a new tragic fibromyalgia model

Investigadores independientes han descrito la emergencia de un síndrome doloroso-disautonómico crónico enseguida de la vacunación contra el virus del papiloma humano (VPH). La veracidad de este síndrome es objeto de un encendido debate. Muchos de los casos reportados cumplen los criterios diagnósticos de fibromialgia. Este artículo discute los argumentos a favor de la existencia de este nuevo síndrome. Propone que el modelo neuropático-disautonómico de la fibromialgia podría ayudar en el proceso diagnóstico y terapéutico de los casos que presentan un padecimiento doloroso crónico después de haber sido inmunizados frente al VPH. Por otro lado, de corroborarse su veracidad, el síndrome posvacunal VPH se erigiría como un nuevo modelo trágico e indeseado de fibromialgia

Independent investigators have described the onset of a chronic painful dysautonomic syndrome soon after human papillomavirus (HPV) vaccination. The veracity of this syndrome is hotly debated. Many of the reported post-HPV vaccination cases fullfill fibromyalgia diagnostic criteria. This article discusses the arguments favoring the existence of a syndrome associated to HPV vaccination. We propose that fibromyalgia dysautonomic-neuropathic model could help in the diagnostic and therapeutic process in those patients in whom the onset of a painful chronic illness began after HPV immunization. On the other hand, if its veracity is corroborated, HPV vaccination syndrome may become a new tragic fibromyalgia model

Síndrome de dolor regional complejo asociado a terapia con eritropoyetina / Complex regional pain syndrome associated with erythropoietin therapy

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Pramipexole-induced limb dystonia and its associated complex regional pain syndrome in idiopathic Parkinson's disease: A case report.

RATIONALE: This case may be due to basal ganglia dysfunction, which was probably caused by abnormal activation of dopamine 1-like receptor (D1R) boosted by pramipexole binding on dopamine 3-like receptor (D3R) in a situation where D3R was overexpressed by the chronic treatment of L-dopa. PATIENT CONCERNS: Striatal hand and foot deformities. DIAGNOSES: Striatal hand and foot deformities with CRPS. INTERVENTIONS: Steroid treatemnt and withdrawal of the pramipexole. OUTCOMES: Recovered significantly. LESSONS: Since the degree of overexpression of D3R is increased in a high dose of pramipexole, for patients with PD who are treated with L-dopa chronically, a new use of pramipexole and an increase in dose to alleviate the symptoms of PD should be implemented with caution while closely observing the occurrence of drug-induced complications such as dystonia and CRPS.

Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18-Adjuvanted Vaccine Post-Licensure Data.

Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix®) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review. The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV-16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature. There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV-16/18 vaccination.

A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome.

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS.

Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.

In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of ß2-adrenergic receptor (ß2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1ß, tumor necrosis factor (TNF)-α, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective ß2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective ß2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1ß, TNF-α, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates ß2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.

Development of a complicated pain syndrome following cyanide poisoning in a U.S. soldier.

A majority of modern war wounds are caused by blasts and high-energy ballistics. Extremity injuries predominate since modern body armor does not protect these areas due to mobility limitations. A less known and more insidious mechanism of enemy attack among our soldiers involves treachery by the local populace posing as noncombatants. One such recent event involved the contamination of tobacco with cyanide (CN). We describe a case of a soldier with CN intoxication due to ingestion of tobacco purchased from a local merchant. The soldier developed a complex neuropathic pain syndrome and was successfully treated with an inpatient high-dose intravenous ketamine infusion in combination with continuous peripheral nerve blockade.

Infiltration and extravasation.

The Infusion Nurses Society's national standards of practice require that a nurse who administers IV medication or fluid know its adverse effects and appropriate interventions to take before starting the infusion. A serious complication is the inadvertent administration of a solution or medication into the tissue surrounding the IV catheter--when it is a nonvesicant solution or medication, it is called infiltration; when it is a vesicant medication, it is called extravasation. Both infiltration and extravasation can have serious consequences: the patient may need surgical intervention resulting in large scars, experience limitation of function, or even require amputation. Another long-term effect is complex regional pain syndrome, a neurologic syndrome that requires long-term pain management. These outcomes can be prevented by using appropriate nursing interventions during IV catheter insertion and early recognition and intervention upon the first signs and symptoms of infiltration and extravasation. Nursing interventions include early recognition, prevention, and treatment (including the controversial use of antidotes, and heat and cold therapy). Steps to manage infiltration and extravasation are presented.

Continuous intra-arterial application of substance P induces signs and symptoms of experimental complex regional pain syndrome (CRPS) such as edema, inflammation and mechanical pain but no thermal pain.

Substance P is involved in nociception in both the peripheral nervous system and the CNS and has been documented to play a crucial role in the complex regional pain syndrome (CRPS). So far, however, most experimental animal models are restricted to the effect of neurokinin-1 receptor blockers to inhibit substance P and do not directly evaluate its action. Thus, this study was conducted to test the hypothesis that local application of substance P causes signs and symptoms of CRPS. For this purpose rats received a continuous infusion of either substance P or saline over 24 h delivered by a mini-osmotic pump connected to an intrafemoral catheter. Animals were analyzed at either day 1 (n=6, each group) or day 4 (n=5, each group) after start of infusion. Substance P application caused a significant and long-lasting decrease in paw withdrawal thresholds upon mechanical stimulation, while animals did not present with thermal allodynia at days 1 and 4 after onset of infusion. In addition, severe s.c. edema was observed in all animals receiving substance P. In vivo fluorescence microscopy of the extensor digitorum longus muscle of the affected hind paw revealed enhanced leukocyte-endothelial cell interaction with a significant rise in the number of leukocytes both rolling along and firmly adhering to the wall of postcapillary venules, while saline-exposed animals were free of this local inflammatory response. Muscle cell apoptosis, as assessed by in vivo bisbenzimide staining, terminal deoxynucleotidyl transferase nick end labeling analysis and caspase 3-cleavage, could not be observed in either of the animals. In summary, the present study indicates that substance P is responsible for neurogenic inflammation, including local cell response, edema formation and mechanical pain, while it seems not to contribute to the generation of thermal allodynia.