Involvement of microglial cells in the antinociceptive effects of metamizol in a mouse model of neuropathic pain.

Metamizol (also known as dipyrone or sulpyrine) is one of the non-opioid analgesics commonly used in clinical practice in the treatment of somatic and visceral pain. Here, our results give evidence that repeated twice daily intraperitoneal metamizol administration during 7 days diminished development of neuropathic pain symptoms in a mouse model of neuropathic pain. We observed that metamizol inhibited the activation of spinal microglia in neuropathic mice. Moreover, our findings provide evidence that pronociceptive (IL-1ß, XCL1, and CCL2), but not antinociceptive (IL-1α, IL-1RA, and IL-18BP), factors play an important role in metamizol-induced antinociception. We observed that metamizol influences the spinal levels of the nociceptin receptor (NOP) but does not alter the expression of other members of the opioid receptor family (mu (MOP), delta (DOP) and kappa (KOP)), or other important nociception receptors (transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1)). Metamizol administration did not affect the levels of the opioid prohormones (proopiomelanocortin (POMC), proenkephalin (PENK), prodynorphin (PDYN), and pronociceptin (PNOC)). However, we observed an enhanced antinociceptive effect of oxycodone, but not buprenorphine, after metamizol treatment. In conclusion, we found that metamizol-induced analgesia in neuropathy is associated with silencing microglia activation and, consequently, with a reduction in pronociceptive cytokines. These results provide evidence that metamizol may join the modest arsenal of effective remedies for neuropathic pain and may constitute part of a multimodal pain therapy.

Pathophysiology and clinical characteristics of pain in most common locations in cancer patients.

Pain is one of the most common symptoms in cancer patients, especially in advanced disease. However, pain also accompanies a significant percentage of patients during diagnostic and therapeutic procedures. In some patients pain may be the first symptom of the disease. The causes of pain in cancer patients are often multifactorial including direct and indirect cancer effects, anticancer therapy and co-morbidities. Moreover, pain in cancer patients often has mixed pathophysiology including both nociceptive and neuropathic components, especially in patients with bone metastases. In this article, basic knowledge regarding epidemiology, pathophysiology and clinical features of pain in cancer patients with a primary tumour localised in lung, gastrointestinal tract (stomach, colon and pancreas), breast in women and prostate in men are presented. Pain is a common symptom in cancer patients and its appropriate assessment and treatment may significantly improve in patients' and families' quality of life.

Exogenous melatonin abolishes mechanical allodynia but not thermal hyperalgesia in neuropathic pain. The role of the opioid system and benzodiazepine-gabaergic mechanism.

Melatonin (MT) is a neurohormone synthesized and secreted by the pineal gland. MT plays an important role in the regulation of physiological and neuroendocrine functions. The purpose of this study was to assess the overall effect of melatonin on neuropathic pain, the type of melatonin receptor involved, and potential role of the opioid system and GABA(A) receptors. The experiments were conducted by using the animal neuropathic pain model (CCI). The rats with CCI showed the characteristic for the mechanical allodynia and thermal hyperalgesia signs that were calculated by using the von Frey's and Hargreaves' tests. The conducted studies measured the effects of intraperitoneal administration of naloxone (opioid antagonist), prazosin (MT3 antagonist), luzindole (MT1/MT2 receptor antagonist), picrotoxin (GABA(A) antagonist) and flumazenil (benzodiazepine antagonist) on the antinociceptive effects caused by melatonin. Melatonin caused the increase in the pain threshold of the mechanical allodynia and the slight increase in the threshold of the thermal hyperalgesia. The pre-treatment with naloxone completely abolished the antinociceptive effects of melatonin in von Frey's test, but not thermal sensation in the Hargreaves's test. Prazosin did not have any effects, while administration of luzindole significantly suppressed the antinociceptive effect of melatonin. The antiallodynic effect of MT was also abolished by flumazenil and picrotoxin. Melatonin influences the mechanical allodynia but not thermal hyperalgesia via activation of opioid system and benzodiazepine-GABAergic pathway. Antinociceptive effects of melatonin are mostly related to the MT1/MT2 receptors interaction.

Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain: an isobolographic analysis.

Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. Tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED(50) doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.

Intrathecal administration of doxepin attenuated development of formalin-induced pain in rats.

The aim of the present research was to assess the influence of a tricyclic antidepressant doxepin administered intrathecally (i.t.) on the pain behavior in the formalin test (100 microl of 12% formalin was injected into the dorsal part of the hind paw under halotane anesthesia) in male Wistar rats. The influence of doxepin (62.5 microg i.t.) on the pain threshold and number of formalin-induced pain behaviors, as well as antinociceptive effect of morphine was studied. Doxepin significantly increased the nociceptive threshold in the paw pressure test, reduced formalin-induced pain behavior and potentiated morphine antinociceptive effect in formalin test. The obtained results indicate that analgesic effect of doxepin used before the injury is observable at the spinal level after intrathecal treatment, but not only after peripheral administration, which was shown in our previous study. The results of the present research demonstrated a possibility to modify the spinal nociceptive process by administration of doxepin before the formalin injection.

Influence of pre-operative ketoprofen administration (preemptive analgesia) on analgesic requirement and the level of prostaglandins in the early postoperative period.

The aim of this study was to examine the effect of ketoprofen used in preemptive analgesia on the intensity of pain and requirement for analgesics in the perioperative period. Sixty patients scheduled for elective lumbar disc prolapse surgery were randomly divided into two groups. In the PRE group (n = 30) ketoprofen was administered one hour before incision. In the POST group ( n = 30) ketoprofen was used immediately after the surgery. The operation was performed under general anesthesia. Postoperative analgesia was realized by NCA (Nurse Controlled Analgesia) and the "required" dose of ketoprofen was 100 mg. After the operation, pain intensity was measured using visual-analog scale (VAS), ketoprofen requirements, the time to the first dose of ketoprofen, and levels of prostaglandin E(2) (PEG(2)) in blood serum were compared. There were no differences between the groups in the VAS pain scores, and levels of PGE(2) in blood serum. However, in patients of PRE group who had received preemptive analgesia, a significantly lower total consumption of ketoprofen, as compared with POST group, was observed between 12th and 36th postoperative hours. It was also found that the time which elapsed between the end of the operation and the first NCA activation was significantly shorter in the PRE group, as compared with the POST group. The results of our study confirm the possibility of modifying the nociception process in the perioperative period through preemptive analgesia by ketoprofen.

Pentoxifylline does not affect nociception if administered postoperatively.

Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6), act as mediators of post-injury inflammation and increase pain sensitivity. Pentoxifylline (PTX) has the property of inhibiting TNF-alpha, IL-1, and IL-6 production. Previous studies revealed that the pre-injury or preoperative administration of PTX inhibited consequent hyperalgesia or postoperative pain. The aim of the study was to determine, if postoperative PTX administration affects postoperative pain. A group of 40 patients undergoing laparotomic cholecystectomy received postoperatively PTX at 10 mg/kg or placebo directly after the termination of general anesthesia. There were no differences in postoperative pain, analgesic drug requirement or TNF-alpha and IL-6 serum levels between the groups.

Influence of doxepin used in preemptive analgesia on the nociception in the perioperative period. Experimental and clinical study.

The aim of the present research was to assess in experimental and clinical study the influence of doxepin administered intraperitoneally (ip) as preemptive analgesia on the nociception in the perioperative period. The pain thresholds for mechanical stimuli were measured in rats. The objective of clinical investigation was to assess the influence of preemptive administration of doxepin on postoperative pain intensity, analgesic requirement in the early postoperative period as well as an assessment of the quality of postoperative analgesia by the patient. Doxepin injected ip (3-30 mg/kg) dose-dependently increased the pain threshold for mechanical stimuli measured in paw pressure test in rats. Doxepin injected 30 min before formalin significantly increased the nociceptive threshold in the paw pressure test. In contrast, doxepin injected 240 min before formalin or 10 min after formalin did not change the nociceptive threshold. Morphine administered subcutaneously (sc) at a dose of 1 mg/kg increased the pain threshold measured in the paw pressure test 55 min after formalin treatment. Injection of 10 mg/kg of doxepin 30 min before formalin further enhanced the response after morphine administration. The results of the clinical study demonstrated that the patients who were administered doxepin preemptively showed significantly lower pethidine requirement in order to achieve a similar level of postoperative analgesia. The results of the research under discussion confirm the theoretical assumptions that there is a possibility to modify the nociception process in the perioperative period through preemptive analgesia using a drug that modifies the activity of the descending antinociceptive system.

[Pathophysiology of postoperative pain]. / Patofizjologia bólu pooperacyjnego.

The rapid progress in neurophysiology and neuropharmacology has made it possible to understand an entire series of pain-related processes. The discovery of endogenic opioid system, the noradrenergic and serotoninergic antinociceptive systems, peripheral opioid receptors and of the role of NMDA, muscarinic and nicotinic receptors in nociception allowed for an optimization of pain treatment through the use of new drugs and therapies. An appropriate pain treatment procedure prevents the development of persistent postoperative pain, which is described as a pathological chronic pain that endures following the operation despite normal healing process having taken place in affected tissues.

[Pharmacotherapy of postoperative pain]. / Farmakoterapia bólu pooperacyjnego.

In recent years there has been much progress in the understanding of the pathophysiology of acute pain and analgesic pharmacology. The most important role in postoperative pain management is still played by opioids administered through various modes, including spinal and local ones. However, non-opioid analgesics, i.e. non-steroid anti-inflammatory drugs and paracetamol are more and more frequently used in the management of postoperative pain, which is the result of, among other factors, the appearance on the market of intravenous forms of those drugs. Paracetamol, owing to its safe therapeutical profile, should be the primary postoperative pain management tool in a majority of surgical procedures. A combination of opioids, NSAIDs and paracetamol in order to relieve pain allows both for a significant reduction in the dosage of respective drugs, fewer side effects and an improved pain relief.

[Postoperative pain treatment]. / Metody stosowane w usmierzaniu bólu pooperacyjnego.

Postoperative pain, arising due to surgical tissue injury, is most frequent type of pain found in clinical practice. In postoperative analgesia opioids still constitute the fundamental form of pain treatment, but the development of neurophysiology and neuropharmacology has allowed for the optimization of postoperative analgesia. Therefore, in order to potentialize the pain relief effect of opioids and/or inhibit the nociception process and its consequences, diverse drugs and therapies are used. The procedure is called multimodal analgesia and consists in the administration of opioids in conjunction with NMDA antagonists, COX inhibitors, cholecystokinin antagonists, agonists of muscarine receptors, agonists of alpha-2 receptors or cytokine inhibitors. An alternative or supplementary therapy in the postoperative period relies on local anaesthetic techniques or TENS. There also exists pre-emptive analgesia, whose aim is to safeguard the central nervous system from increased afferent nociceptive stimulation during the operation.

The effect of pentoxifiline on post-injury hyperalgesia in rats and postoperative pain in patients.

Recent studies demonstrate that activation of proinflammatory cytokines following injury intensifies the process of nociception. The present investigation assessed the influence of pre-injury pentoxifiline (PTFL, a non-specific cytokine inhibitor) on the development of post-injury nociception in animals and patients. It was established that intrathecal or intraperitoneal PTFL, elevated the nociceptive threshold for mechanical stimuli in the formalin test in rats. Pre-injury PTFL also inhibited pain-related behaviour. These findings correlate with a lower TNFalpha level in the serum of animals receiving pre-injury PTFL. In clinical investigations PTFL was administered intravenously before elective cholecystectomy. Patients who received preoperative PTFL had lower opioid requirements in the early postoperative period than control. At the same time, serum levels of TNFalpha and IL6 were lower in the PTFL group. Our results confirm the hypothesis as to the possibility of modulating of nociception through preemptive administration of a cytokine inhibitor.

[Respiratory infections in the surgical intensive care unit]. / Zakazenia ukladu oddechowego w oddziale chirurgicznej intensywnej terapii.

The purpose of the study was to assess microbiological structure and the influence of the predisposing factors on frequency of lower respiratory tract infections. The study group consisted of 72 patients admitted to the Intensive Care Unit between January and October 1994. We found that 27 pts. (39%) developed respiratory infections. The risk of an infection was much higher in the group with long (over 5 days) stay on ICU, which required artificial ventilation as well as in the group of patients treated due to acute pancreatitis. More than 75% of isolated strains were Gram negative bacteria. Using susceptibility tests we conclude that Pseudomonas aeruginosa, Serratia, and Acinetobacter baumanii are highly resistant to antibiotics. The results suggests that 3rd generation cephalosporins and imipenem are most efficient in vitro.