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- Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain. [JOURNAL ARTICLE]
- Pflugers Arch 2014 Nov 26.
Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.
- Electrochemical simulation of cocaine metabolism-a step toward predictive toxicology for drugs of abuse. [Journal Article, Research Support, Non-U.S. Gov't]
- Eur J Mass Spectrom (Chichester, Eng) 2014; 20(4):279-85.
Knowledge of the metabolic pathways and biotransformation of the most popular drugs, such as cocaine, amphetamine, morphine and others, is crucial for the elucidation of their possible toxicity and mechanism of action in the human body. In vitro studies on metabolism are mainly based on the incubation of drugs with liver celL homogenate and utilizing Living animals. These methods need to be followed by isolation and detection of metabolic products, which makes these techniques time-consuming and technically demanding. We show here that the oxidative metabolism that occurs in the liver cells and is mainly caused by cytochrome P450 can be successfully mimicked with the electrochemical system [EC] connected on-line with electrospray ionization mass spectrometry. Cocaine was chosen as a model drug for these studies and was analyzed with a previously described system under various conditions using the boron-doped diamond working electrode. The results were compared with the number of metabolites generated by a standard procedure based on the reaction with the rat Liver microsomes. Two electrochemical products of cocaine oxidation were created, of which one was a natural metabolite of cocaine in the human body-norcocaine. The EC provides a promising platform for the screening of the addictive drug phase I metabolism. The metabolites can be directly analyzed by mass spectrometry or collected and separated by Liquid chromatog- raphy. No Liver cell homogenate or microsome is necessary to generate these metabolites, which simplifies separation of the mixtures and reduces time and costs of all experiments.
- Thin Layer Chromatography-Ion Mobility Spectrometry (TLC-IMS). [JOURNAL ARTICLE]
- Anal Chem 2014 Nov 24.
Ion mobility spectrometry (IMS) is a fast and sensitive analytical method which operates at the atmospheric pressure. To enhance the capability of IMS for the analysis of mixtures, it is often used with pre-separation techniques such as GC or HPLC. Here, we report for the first time the coupling of the thin-layer chromatography and IMS. A variety of coupling schemes were tried that included direct electrospray from the TLC strip tip, indirect electrospray from a needle connected to the TLC strip, introducing the moving solvent into the injection port, and, the simplest way, offline introduction of scratched or cut pieces of strips into the IMS injection port. In this study a special solvent tank was designed and the TLC strip was mounted horizontally where the solvent would flow down. A very small funnel right below the TLC tip collected the solvent and transferred it to a needle via a capillary tubing. Using the TLC-ESI-IMS technique, acceptable separations were achieved for two component mixtures of morphine-papaverine and acridine-papaverine. A special injection port was designed to host the pieces cut off the TLC. The method was successfully used to identify each spot on the TLC by IMS in a few seconds.
- Ovariectomy modulation of morphine analgesia of neuropathic pain is associated with the change of K(+)-Cl(-) cotransporter 2 protein level in spinal dorsal horn. [JOURNAL ARTICLE]
- Int J Clin Exp Med 2014; 7(10):3467-3472.
Sex differences in opioid analgesia have been confirmed both in clinical and experimental studies. Gonadal hormones (estrogens in particular) have a great role in this process. However, the mechanisms that underlie these sex differences are not very clear. In this study, we used K(+)-Cl(-) cotransporter 2 (KCC2) as a molecule target to investigate the mechanism underlying the phenomenon. Sprague-Dawley rats were randomly assigned to ovariectomy (OVX)+morphine group, OVX+Saline group, sham surgery (OVX-sham)+morphine group and OVX-sham+saline group. All the rats received SNI surgery three weeks after ovariectomy. We used von Frey values as a sign of neuropathic pain. On PO day 14, 1 μg morphine or the vehicle saline was administered intrathecally via a PE-10 catheter formerly implanted. Hindpaw withdrawal threshold was determined before and 30, 60, 90, 120, 150, 180 min after drugs injection. The L4-L5 segments of the spinal cord were removed and immunoblotted for KCC2 protein at the time of 2 and 3 h after drugs administration. We find that ovariectomy can regulate the sensitivity to morphine analgesia of neuropathic pain and KCC2 protein level will change in the spinal dorsal horn.
- Practical considerations and patient selection for intrathecal drug delivery in the management of chronic pain. [REVIEW]
- J Pain Res 2014.:627-638.
Chronic pain continues to pose substantial and growing challenges for patients, caregivers, health care professionals, and health care systems. By the time a patient with severe refractory pain sees a pain specialist for evaluation and management, that patient has likely tried and failed several nonpharmacologic and pharmacologic approaches to pain treatment. Although relegated to one of the interventions of "last resort", intrathecal drug delivery can be useful for improving pain control, optimizing patient functionality, and minimizing the use of systemic pain medications in appropriately selected patients. Due to its clinical and logistical requirements, however, intrathecal drug delivery may fit poorly into the classic pain clinic/interventional model and may be perceived as a "critical mass" intervention that is feasible only for large practices that have specialized staff and appropriate office resources. Potentially, intrathecal drug delivery may be more readily adopted into larger practices that can commit the necessary staff and resources to support patients' needs through the trialing, initiation, monitoring, maintenance, and troubleshooting phases of this therapy. Currently, two agents - morphine and ziconotide - are approved by the United States Food and Drug Administration for long-term intrathecal delivery. The efficacy and safety profiles of morphine have been assessed in long-term, open-label, and retrospective studies of >400 patients with chronic cancer and noncancer pain types. The efficacy and safety profiles of ziconotide have been assessed in three double-blind, placebo-controlled trials of 457 patients, and safety has been assessed in 1,254 patients overall, with severe chronic cancer, noncancer, and acquired immunodeficiency syndrome pain types. Both agents are highlighted as first-line intrathecal therapy for the management of neuropathic or nociceptive pain. The purpose of this review is to discuss practical considerations for intrathecal drug delivery, delineate criteria for the identification and selection of candidates for intrathecal drug delivery, and consider which agent may be more appropriate for individual patients.
- The last three days of life: a comparison of pain management in the young old and the oldest old hospitalised patients using the Resident Assessment Instrument for Palliative Care. [JOURNAL ARTICLE]
- Int J Older People Nurs 2014 Nov 22.
Pain is a common symptom in older patients at the end of life. Little research has evaluated pain management among the oldest hospitalised dying patients.To compare the pain characteristics documented by healthcare workers for the young old and the oldest old hospitalised patients and the types of analgesics administered in the last three days of life.A retrospective cross-sectional comparative study.The study included 190 patients from a Norwegian general hospital: 101 young old patients (aged 65-84 years) and 89 oldest old patients (aged 85-100 years). Data were extracted from electronic patient records (EPRs) using the Resident Assessment Instrument for Palliative Care.No significant differences were found between the young old and the oldest old patients with regard to pain characteristics. Pain intensity was poorly recorded in the EPRs. Most of the patients received adequate pain control. Morphine was the most frequently administered analgesic for dying patients. Compared to the oldest old patients, a greater proportion of the young old patients received paracetamol combined with codeine (OR = 3.25, 95% CI 1.02-10.40).There appeared to be no differences in healthcare workers' documentation of pain characteristics in young old and oldest old patients, but young old patients were more likely to receive paracetamol in combination with codeine.A limitation of the study is the retrospective design and that data were collected from a single hospital. Therefore, caution should be taken for interpretation of the results. The use of systematic patient-reported assessments in combination with feasible validated tools could contribute to more comprehensive documentation of pain intensity and improved pain control.
- Preoperative opioid use and its association with perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery. [Journal Article]
- Spine (Phila Pa 1976) 2014 Dec 1; 39(25):E1524-30.
Prospective cohort.To assess whether preoperative opioid use is associated with increased perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery.Previous work has demonstrated increased opioid requirements during the intraoperative and immediate postoperative period in patients with high levels of preoperative opioid use. Despite this, they remain a common agent class used for the management of pain in patients prior to spine surgery.A total of 583 patients were included. Self-reported daily opioid consumption was obtained preoperatively and converted into morphine equivalent amounts and opioid use was recorded at the 12-month postoperative time. Intraoperative and immediate postoperative opioid demand was calculated. Linear regression analyses for intraoperative and immediate postoperative opioid demand while logistic regression analyses for opioid independence at 12 months including relevant covariates such as depression and anxiety were performed.The median preoperative morphine equivalent amount for the cohort was 8.75 mg, with 55% of patients reporting some degree of opioid use. Younger age, more invasive surgery, anxiety, and primary surgery were significantly associated with increased intraoperative opioid demand (P < 0.05). Younger age, anxiety, and greater preoperative opioid use were significantly associated with increased immediate postoperative opioid demand (P < 0.05). More invasive surgery, anxiety, revision surgery, and greater preoperative opioid use were significantly associated with a decreased incidence of opioid independence at 12 months postoperatively (P < 0.01).Greater preoperative opioid use prior to undergoing spine surgery predicts increased immediate postoperative opioid demand and decreased incidence of postoperative opioid independence. Psychiatric diagnoses in those using preoperative opioids were predictors of continued opioid use at 12 months. Patients may benefit from preoperative counseling that emphasizes minimizing opioid use prior to undergoing spine surgery.2.
- ACOEM Practice Guidelines: Opioids for Treatment of Acute, Subacute, Chronic, and Postoperative Pain. [JOURNAL ARTICLE]
- J Occup Environ Med 2014 Nov 20.
The American College of Occupational and Environmental Medicine's guidelines have been updated to develop more detailed guidance for treatment of acute, subacute, chronic, and postoperative pain with opioids.Literature searches were performed using PubMed, EBSCO, Cochrane Review, and Google Scholar without publication date limits. Of 264,617 articles' titles screened and abstracts reviewed, 263 articles met inclusion criteria. Of these, a total of 157 were of high and moderate quality addressing pain treatment. Comprehensive literature reviews were accomplished with article abstraction, critiquing, grading, evidence table compilation, and guideline finalization by a multidisciplinary expert panel to develop evidence-based guidance.No quality evidence directly supports histories, physical examinations, and opioid treatment agreements, although they are thought to be important. No quality trials were identified showing superiority of opioids, compared with nonsteroidal anti-inflammatory and other medications for treatment of chronic, noncancer pain. The use of opioid-sparing treatments associated with lower doses of postoperative opioids is also associated with better long-term functional outcomes. Selective use of opioids is recommended for patients with acute and postoperative pain. Consensus recommendations also include consideration of carefully conducted trials of chronic opioid treatment for highly select patients with subacute and chronic pain and to maintenance opioid prescriptions only if documented objective functional gain(s) results. A strong and reproducible dose-response relationship identifies a recommended morphine equivalent dose limit of no more than 50 mg/day. Higher doses should be prescribed only with documented commensurately greater functional benefit(s), comprehensive monitoring for adverse effects, informed consent, and careful consideration of risk versus benefit of such treatment. Chronic opioid use should be accompanied by informed consent, a treatment agreement, tracking of functional benefits, drug screening, and attempts at tapering.
- Effect of morphine on the persistence of long-term memory in rats. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Nov 22.
Current evidence suggests that pharmacological manipulation around 12 h after training alters the persistence of long-term memory. However, no study has addressed whether opioids modulate the persistence of fear. The current study examined whether morphine alters the persistence of the memory of contextual fear conditioning.Male adult Wistar rats were injected with saline (NaCl 0.9 %, intraperitoneally (i.p.)) or morphine (3 and/or 10 mg/kg, i.p.) 6, 9, 12, or 24 h post-training and tested 2 or 7 days after training, when freezing responses were assessed. The involvement of state dependence and opioid receptors in the effect of morphine was investigated by respectively injecting naloxone (1 mg/kg, i.p.) 30 min before morphine, and morphine (10 mg/kg, i.p.) 30 min before testing.Morphine (10 mg/kg, i.p., 12 h post-training) did not alter freezing to context in animals tested 2 days after training but impaired freezing to context when testing was carried out 7 or 14 days after training. Morphine (10 mg/kg, i.p.) administration 6, 9, or 24 h post-training did not alter freezing measured 2 or 7 days after training. Pre-test morphine improved recall but did not alter the deleterious effect of 12 h post-training morphine. The deleterious effect of morphine was prevented by naloxone, indicating that opioid receptors are involved in this effect.Our findings indicate an inhibitory role for opioid receptors in memory persistence. This is relevant from both the experimental and clinical point of views, since it may have implications for the prevention of post-traumatic stress disorder (PTSD).
- Acute Generalized Exanthematous Pustulosis Caused by Dihydrocodeine Phosphate in a Patient With Psoriasis Vulgaris and a Heterozygous IL36RN Mutation. [JOURNAL ARTICLE]
- JAMA Dermatol 2014 Nov 19.
Acute generalized exanthematous pustulosis (AGEP) is a rare and severe type of drug eruption. Dihydrocodeine phosphate is a semisynthetic opioid analgesic. Recently, recessive mutations in IL36RN have been identified in generalized pustular psoriasis (GPP). To date, 4 cases of AGEP and IL36RN mutation without previous history of psoriasis vulgaris (PV) have been reported.A woman in her 60s with PV presented with diffuse erythema, nonfollicular pustules, and fever. She had been treated with dextromethorphan hydrobromide hydrate, amoxicillin hydrate, clarithromycin, dihydrocodeine phosphate, tipepidine hibenzate, and tulobuterol tape for a cough and common cold. Based on histopathologic results and a positive result in a drug provocation test with dihydrocodeine phosphate, she was diagnosed with AGEP. A heterozygous IL36RN mutation c.28C>T (p.Arg10X) was also confirmed by mutation analysis.This is the first report of dihydrocodeine phosphate-induced AGEP. In this case, helper T cells, type 17, might have been activated because of morphine and underlying PV, followed by increased production of interleukin (IL) 36. However, because of the IL36RN mutation, IL-36 signaling was uncontrolled, which might have resulted in the occurrence of AGEP. An IL36RN mutation might underlie several different pustular skin eruptions, including AGEP and GPP, and further accumulation of patient data is required.