Treatment Of Pain In Humans Research Articles

Antinociceptive Effects of Paeonia daurica subsp. macrophylla Root Extracts in Mice

This study aimed to assess the antinociceptive activity of extracts and fractions of Paeonia daurica subsp. macrophylla in BALB/c mice. Various doses of hydro-alcoholic extract (HE), hexane fraction (F-hexane), methanol (F-MeOH), and chloroform (F-CHCl3), as well as aqueous extracts (AE), were evaluated by a well-known model, a formalin-induced pain test in mice. All extracts, piroxicam 0.1 mg/kg, and negative control groups were administered 30 minutes before formalin injection. Flinching, licking, and biting reflexes were measured as painful factors compared with controls at intervals of 0 to 5 minutes, 0 to 15, and 0 to 60 minutes after formalin injection. The acute oral toxicity test of total ethanolic and aqueous extracts showed no signs of toxic effect up to a dose of 5000 mg/kg. In the formalin test at a time interval of 0 to 5 minutes, there was no significant difference between the results of the study groups. In the range of 0 to 15 minutes, the effect of AE (1 g/kg), HE (2, 3 g/kg), and F-hexane (1 g/kg) was significantly higher than the positive control group (p<0.01). In the time interval of 0 to 60 minutes as the total time of the experiment, the effect of AE (0.25 g/kg), AE (0.5, 1 g/kg), HE (2, 3 g/kg), F-hexane (1 g/kg) were significantly different than the positive control group. It can be concluded that extract of P. daurica subsp. macrophylla might be helpful in the treatment of pain in humans.

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater.

Pain, usually caused by a strong or disruptive stimulus, is an unpleasant sensation that serves as a warning to organisms. To adapt to extreme environments, some terrestrial animals have evolved to be inherently insensitive to pain. Cetaceans are known as supposedly indifferent to pain from soft tissue injury representatives of marine mammals. However, the molecular mechanisms that explain how cetaceans are adapted to pain in response to seawater environment remain unclear. Here, we performed a molecular evolutionary analysis of pain-related genes in selected representatives of cetaceans. ASIC4 gene was identified to be pseudogenized in all odontocetes (toothed whales) except from Physeter macrocephalus (sperm whales), and relaxed selection of this gene was detected in toothed whales with pseudogenized ASIC4. In addition, positive selection was detected in pain perception (i.e., ASIC3, ANO1, CCK, and SCN9A) and analgesia (i.e., ASIC3, ANO1, CCK, and SCN9A) genes among the examined cetaceans. In this study, potential convergent amino acid substitutions within predicted proteins were found among the examined cetaceans and other terrestrial mammals, inhabiting extreme environments (e.g., V441I of TRPV1 in cetaceans and naked mole rats). Moreover, specific amino acid substitutions within predicted sequences of several proteins were found in the studied representatives of cetaceans (e.g., F56L and D163A of ASIC3, E88G of GRK2, and F159L of OPRD1). Most of the substitutions were located within important functional domains of proteins, affecting their protein functions. The above evidence suggests that cetaceans might have undergone adaptive molecular evolution in pain-related genes through different evolutionary patterns to adapt to pain, resulting in greater sensitivity to pain and more effective analgesia. This study could have implications for diagnosis and treatment of human pain.

A sensitive method for determination of nimesulide and its hydroxy metabolite in milk using validated UPLC-MS method

Nimesulide is a widely used drug for the treatment of pain in humans as well as in animals. The presence of trace amounts of drugs in milk or other food supplement affects seriously human health. This study reports a method based on LC-MS detection for the determination of nimesulide and its hydroxy metabolite in cow milk samples. Waters ACQUITY BEH C18 column (100 mm × 2.1 mm, 1.7 µm), with gradient elution using 0.1% formic acid and acetonitrile as mobile phase at a flow rate of 0.3 mL min−1 was used for the chromatographic separation. The ion scans were quantified at m/z 307.0393 for nimesulide, m/z 323.0375 for hydroxy nimesulide metabolite and m/z 434.2198 for IS (valsartan) in negative ESI mode. A double extraction method with protein precipitation by acetonitrile followed by solid-phase extraction was developed to detect nimesulide at 1.30 ng mL−1 and hydroxy nimesulide at 1.03 ng mL−1 in milk. The calibration curve was constructed for nimesulide in the range of 1.30 ng mL−1 to 125.07 ng mL−1 while for hydroxy nimesulide calibration curve was constructed in the range of 1.03 ng mL−1 to 99.70 ng mL−1 in whole cow milk without any treatment. The validation parameters like accuracy, precision, selectivity, stability, matrix effect and dilution integrity were also performed on nimesulide and hydroxy nimesulide. The developed processing and chromatographic method can be used to quantitatively determine nimesulide or its hydroxy nimesulide metabolite in biological matrices, i.e., milk, plasma, faecal, tissue, etc.

Oxycodone decreases anxiety-like behavior in the elevated plus-maze test in male and female rats.

The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those without one. Therefore, oxycodone might be misused for its anxiolytic properties. We investigated if oxycodone affects anxiety-like behavior in adult male and female rats. The rats were treated with oxycodone (0.178, 0.32, 0.56, or 1 mg/kg), and anxiety-like behavior was investigated in the elevated plus-maze test. Immediately after the elevated plus-maze test, a small open field test was conducted to determine the effects of oxycodone on locomotor activity. In the elevated plus-maze test, oxycodone increased the percentage of time spent on the open arms, the percentage of open arm entries, time on the open arms, open arm entries, and the distance traveled. The males treated with vehicle had a lower percentage of open arm entries than the females treated with vehicle, and oxycodone treatment led to a greater increase in the percentage of open arm entries in the males than females. Furthermore, the females spent more time on the open arms, made more open arm entries, spent less time in the closed arms, and traveled a greater distance than the males. In the small open field test, treatment with oxycodone did not affect locomotor activity or rearing. Sex differences were observed; the females traveled a greater distance and displayed more rearing than the males. In conclusion, oxycodone decreases anxiety-like behavior in rats, and oxycodone has a greater anxiolytic-like effect in males than females.

Pharmacokinetic profiles of the analgesic flupirtine in dogs after the administration of four pharmaceutical formulations

ObjectiveFlupirtine (FLU) is a non-opioid analgesic with no antipyretic or anti-inflammatory effects which is used in the treatment of pain in humans. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate for the recommendation of its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after intravenous (IV), oral immediate release (POIR), oral prolonged release (POPR) and rectal (RC) administrations in healthy dogs. Study designFour-treatment, single-dose, four-phase, unpaired, cross-over design (4 × 4 Latin-square). AnimalsSix adult Labrador dogs. MethodsAnimals in groups 1, 2 and 4 received a single dose of 5 mg kg−1 FLU administered by IV, POIR and RC routes. Group 3 received a single dose of 200 mg subject−1 via the POPR route. The wash-out periods were 1 week. Blood samples (1 mL) were collected at assigned times for 48 hours and plasma FLU concentrations were analysed by a validated HPLC method. ResultsAdverse effects including salivation, tremors and vomiting were noted in the IV group and resolved spontaneously within 10 minutes. These effects did not occur in the other groups. The FLU plasma concentrations were detectable in all of the treatment groups for 36 hours following administration. The pharmacokinetic profiles after extravascular administrations showed similar trends. The bioavailability values after POIR, POPR and RC were 41.93%, 36.78% and 29.43%, respectively. There were no significant differences in pharmacokinetic profiles between the POIR and POPR formulations. A 5 mg kg−1 POIR dose or a 200 mg subject−1 POPR dose gave plasma concentrations similar to those reported in humans after clinical dosing. Conclusion and clinical relevanceThis study provides pharmacokinetic data that can be used to design further studies to investigate FLU in dogs.

It might be a big family but the pain remains—last chance saloon for selective 5-HT receptor ligands?

The following brief overview reflects our own opinion of where the most likely advances to treating pain (unrelated to IBS and migraine) may come from with respect to ligands directly interacting with specific 5-HT receptors. It is fully appreciated, and possibly more likely, that 5-HT plays a modulatory role in the mediation of analgesic effects of certain compounds, for example tricyclic antidepressants and the newer, safer class of serotonin/noradrenaline re-uptake inhibitors, for example duloxetine and milnacipran. However, we find that recent pre-clinical findings highlight the potential of peripherally acting 5-HT(1) and 5-HT(2A) receptor agonists and centrally penetrating 5-HT(7) receptor agonists to reduce chronic pain. We encourage experimentation using human tissues and healthy volunteers to improve the confidence in rationale of targeting such receptors for treatment of pain in humans. However for this to happen the available pharmacological toolbox will also need to be further improved and any safety concerns understood to provide the necessary impetus to go to the clinic.

Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain

Spinal administration of GABA(A) receptor modulators, such as the benzodiazepine drug diazepam, partially alleviates neuropathic hypersensitivity that manifests as spontaneous pain, allodynia, and hyperalgesia. However, benzodiazepines are hindered by sedative impairments and other side effect issues occurring mainly as a consequence of binding to GABA(A) receptors containing the alpha(1) subunit. Here, we report on the novel subtype-selective GABA(A) receptor-positive modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of alpha(5) > alpha(3) > alpha(2) > alpha(1) at GABA(A) alpha subunit-containing receptors. Oral administration of NS11394 (1-30 mg/kg) to rats attenuated spontaneous nociceptive behaviors in response to hindpaw injection of formalin and capsaicin, effects that were blocked by the benzodiazepine site antagonist flumazenil. Ongoing inflammatory nociception, observed as hindpaw weight-bearing deficits after Freund's adjuvant injection, was also completely reversed by NS11394. Likewise, hindpaw mechanical allodynia was fully reversed by NS11394 in two rat models of peripheral neuropathic pain. Importantly, NS11394-mediated antinociception occurred at doses 20 to 40-fold lower than those inducing minor sedative or ataxic impairments. In contrast, putative antinociception associated with administration of either diazepam, zolpidem, or gaboxadol only occurred at doses producing intolerable side effects, whereas bretazenil was completely inactive despite minor influences on motoric function. In electrophysiological studies, NS11394 selectively attenuated spinal nociceptive reflexes and C-fiber-mediated wind-up in vitro pointing to involvement of a spinal site of action. The robust therapeutic window seen with NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of pain in humans.

Enhanced Peripheral Analgesia Using Virally Mediated Gene Transfer of the μ-Opioid Receptor in Mice

The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the mu-opioid receptor (muOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. Cutaneous inoculation with herpes simplex virus containing muOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of muOR in primary afferents. The effects of altered muOR levels on peripheral analgesia were then examined. At 4 weeks after SGAMOR and SGMOR infection, decreased and increased muOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in muOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.

Pain signalling pathways: From cytokines to ion channels

Pain is the major reason patients seek medical care. The treatment of pain, particularly chronic pain associated with cancer and damage to the nervous system, is at present inadequate. Lack of effective analgesics is partly due to the fact that pain signalling mechanisms are still not fully understood. Over the recent years, many channels, receptors, and regulatory proteins involved in pain pathways have bee identified, and novel pain signalling mechanisms and pathways at peripheral and spinal levels have been discovered. It is anticipated that increased understanding of the molecular mechanisms of pain would provide a hope for the future development of effective pain killers. This review examines the currently available information on the molecular aspects of pain signalling pathways, and discusses novel and promising therapeutic targets for the treatment of pain in humans.

Isobolographic analysis of interactions between intravenous morphine, propacetamol, and diclofenac in carrageenin-injected rats.

It has been suggested that the combination of analgesic drugs may have additive or synergistic effects. In clinical practice, this might allow better analgesia and reduction of side effects. The effects of analgesic drugs were studied in a model of acute inflammatory pain in carrageenin-injected rats using the vocalization threshold to paw pressure. A combination of three different intravenous drugs were used: morphine, diclofenac, and propacetamol, a pro-drug of acetaminophen. The dose-response curves were first obtained for each drug alone. The analgesic potencies of the combinations of morphine and diclofenac (ratios, 1:5.66 and 1:10), morphine and propacetamol (ratio, 1:250), and diclofenac and propacetamol (ratio, 1:65.7) were thereafter evaluated and compared with the effects of the drugs alone. For the two different ratios tested, synergy between diclofenac and morphine was observed only with the higher doses. Propacetamol and morphine or diclofenac and propacetamol combinations were additive for all doses tested. This study found a synergy between intravenous morphine and diclofenac that is consistent with and helps explain the clinical value of this type of combination in the treatment of acute pain in humans.

The place of the pain clinic

Chronic pain is a debilitating and degrading condition. Its aetiology is largely multifactorial, and only proper appreciation of the various factors which can combine to produce the patient's misery will allow appropriate therapies. If the mechanisms of chronic pain were better taught and the therapies available were better used by medical practitioners, then the standard of alleviation of pain would increase greatly. There is an urgent need for greatly improved facilities for treating chronic pain by multidisciplinary groups in specialized clinics, a fact which has been realized for over 30 years. However, in spite of this there is a great delay in the setting up of such units. There is also an urgent need for proper training of doctors in pain relief, and a need for a much larger amount of money to be spent on research into the causes and treatment of human pain. It is disturbing to me that so much money goes on research into possible cures of malignant disease in the future, which is all very well, but which does not help the sufferer from severe pain at the present time; whereas these poor unfortunates, dying with their misery unassuaged, must suffer unnecessarily because of lack of information amongst physicians, and lack of proper facilities for treatment. Likewise, our own unit and many others have extremely long waiting lists, making even more difficult the treatment of an already complex problem. In spite of this, more than 50% of patients who attend multidisciplinary pain clinics obtain long-term benefit from their therapy. The fact that facilities do not exist for many sufferers is not only disgraceful, but also very expensive both from social security payments and from inappropriate use of health care facilities as these patients wander from clinic to clinic in search of a cure which is not available. Chronic pain should be recognized for what it is--a severe and debilitating condition--and proper steps should be taken to provide the treatment within the health service for its alleviation.