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- 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.
- Morphine After Tubal Ligation With Bupivacaine: Dosage Versus Body Weight. [JOURNAL ARTICLE]
- JSLS 2014 10; 18(4)
We investigated whether there was a statistically significant difference in patient need for postoperative analgesia based on adjusted body weight between heavier and lighter women who underwent laparoscopic tubal ligation with bupivacaine injection at the skin incision.We examined 49 records of women who underwent laparoscopic tubal ligation at Oklahoma State University Medical Center between 2000 and 2005 and received an injection of bupivacaine at the surgical site during the procedure. Postsurgical morphine was measured as doses per kilogram of body weight against total body weight and as total milligrams per kilogram of body weight against total body weight. A regression was performed for each measurement.Heavier women required significantly fewer total milligrams of morphine per kilogram of body weight and fewer total doses of morphine per kilogram of body weight than lighter women (2-tailed P = .0035 and P = .0018, respectively).Our data may suggest that lipophilic bupivacaine injected at a surgical site is held in place better and works for a longer period when more fat is present.
- Detection of signals of abuse and dependence applying disproportionality analysis. [JOURNAL ARTICLE]
- Eur J Clin Pharmacol 2014 Nov 20.
Prescription drug abuse and dependence is a widespread phenomenon in many countries. The use of disproportionality measures in drug abuse surveillance is rarely performed.The aim of this study is to determine the occurrence of signals of abuse and dependence for different psychoactive drugs in real-life settings.Disproportionality analysis was realised from a database specifically constructed for the monitoring of drug abuse and dependence. This database provides information on approximately 5000 patients and 8000 consumption modalities for more than 100 distinct psychoactive medications for 2010 and 2011. Proportional reporting ratio (PRR) was computed in two population groups: subjects under an opiate maintenance treatment (OMT) versus those not under OMT, and focused on four types of behaviours: abuse and dependence, illegal acquisition, diverted route of administration and concomitant alcohol use.Among the 100 psychoactive drugs for which a signal could be detected, those presenting the highest signals were the following: flunitrazepam, clonazepam, methylphenidate, ketamine, morphine sulfate, codeine and buprenorphine.The present study shows an innovative application of disproportionality measures for drug abuse monitoring based on two cross-national, annual studies. The disproportionality analysis provided the opportunity to reveal and compare the magnitude of signals between 100 psychoactive drugs. This approach helps to compare the magnitude of abuse and dependence behaviours for a large number of drugs, and allows prioritizing actions in a context where such events are usually underreported.
- Effects of Mu Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Rats: Role of Mu Agonist Efficacy and Noxious Stimulus Intensity. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Nov 18.
Pain is associated with stimulation of some behaviors and depression of others, and mu opioid receptor agonists are among the most widely used analgesics for treatment of pain. The present study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six mu opioid analgesics that varied in efficacy at mu opioid receptors (in order from highest to lowest efficacy: methadone, fentanyl, morphine, hydrocodone, buprenorphine, nalbuphine). Intraperitonial injection of dilute lactic acid served as an acute, chemical noxious stimulus to either stimulate a stretching response or depress operant responding maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. All mu agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy mu agonists methadone and fentanyl were more potent to block acid-induced depression of ICSS than acid-stimulated stretching, whereas lower efficacy agonists displayed similar potency across assays. All mu agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy mu agonist nalbuphine, but not the high-efficacy mu agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective mu opioid analgesics and reveal distinctions between opioids based on efficacy at the mu receptor.
- Safety and Tolerability of Gabapentin for Aneurysmal Subarachnoid Hemorrhage (SAH) Headache and Meningismus. [JOURNAL ARTICLE]
- Neurocrit Care 2014 Nov 18.
Headache after aneurysmal subarachnoid hemorrhage (SAH) is very common and is often described as the "worst headache imaginable." SAH-associated headache can persist for days to weeks and is traditionally treated with narcotics. However, narcotics can have significant adverse effects. We hypothesize that gabapentin (GBP), a non-narcotic neuropathic pain medication, would be safe and tolerable and would reduce narcotic requirements after SAH.We retrospectively reviewed the clinical, radiographic, and laboratory data of SAH patients at the neuroscience intensive care unit at Mayo Clinic in Jacksonville, Florida, from January 2011 through February 2013. Headache intensity was quantified by a visual analog scale score. Total opioid use per day was tabulated using an intravenous morphine equivalents scale. Cerebrospinal fluid was also reviewed when available.There were 53 SAH patients who were treated with GBP along with other analgesics for headache. Among these SAH patients, 34 (64 %) were women, with a mean age of 54 years (SD 12.3). Severe headache was observed in all SAH patients. GBP dosing was rapidly escalated within days of SAH up to a median of 1,200 mg/day, with a range of 300 mg three times a day to 900 mg three times a day. Approximately 6 % of patients treated with GBP had nausea (95 % CI 1-16 %), and only one patient (1.8 %) had to discontinue GBP.GBP appears to be relatively safe and tolerable in SAH patients with headache and may be a useful narcotic-sparing agent to prevent narcotics-associated complications, such as gastrointestinal immobility, ileus, and constipation.
- Analgesia for Early-Life Pain Prevents Deficits in Adult Anxiety and Stress in Rats. [JOURNAL ARTICLE]
- Dev Neurosci 2014 Nov 12.
Previous studies in rats have established that inflammatory pain experienced on the day of birth (P0) decreases sensitivity to acute noxious, anxiety- and stress-provoking stimuli. However, to date, the impact of early-life pain on adult responses to chronic stress is not known. Further, the ability of morphine, administered at the time of injury, to mitigate changes in adult behavioral and hormonal responses to acute or chronic stressors has not been examined. P0 male and female Sprague-Dawley rat pups were given an intraplantar injection of 1% carrageenan or handled in an identical manner in the presence or absence of morphine. As adults, rats that experienced early-life pain displayed decreased sensitivity to acute stressors, as indicated by increased time in the inner area of the Open Field, and increased latency to immobility and decreased time immobile in the Forced Swim Test (FST). An accelerated return of corticosterone to baseline was also observed. Morphine administration at the time of injury completely reversed this 'hyporesponsive' phenotype. By contrast, following 7 days of chronic variable stress, injured animals displayed a 'hyperresponsive' phenotype in that they initiated immobility and spent significantly more time immobile in the FST than controls. Responses to chronic stress were also rescued in animals that received morphine at the time of injury. These data suggest that analgesia for early-life pain prevents adult hyposensitivity to acute anxiety- and stress-provoking stimuli and increased vulnerability to chronic stress, and have important clinical implications for the management of pain in infants. © 2014 S. Karger AG, Basel.
- Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats. [JOURNAL ARTICLE]
- Pharmacology 2014 Nov 8; 94(5-6):207-213.
Background: Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. Aim of the Study: To investigate analgesic effects of morphine when co-administered with adjuvant drugs. Material and Methods: Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. Results: Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. Conclusions: Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans. © 2014 S. Karger AG, Basel.
- Selective suppression of microglial activation by paeoniflorin attenuates morphine tolerance. [JOURNAL ARTICLE]
- Eur J Pain 2014 Nov 16.
The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of a natural compound, paeoniflorin, in morphine tolerance via its specific inhibition of microglial activation.The microglia cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. Nociception was assessed in Sprague-Dawley rats and CD-1 mice using Hargreaves' methods or the hot-plate test, respectively.(1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase (MAPK) phosphorylation, nuclear factor (NF)-κB translocation and proinflammatory cytokine expression. These changes are inhibited by paeoniflorin. (2) Co-administration of paeoniflorin with morphine potentiates morphine antinociception by inhibiting p38 MAPK/NF-κB signalling in the spinal cord. (3) Co-administration of paeoniflorin suppresses morphine-increased expression of toll-like receptor-4 both in BV-2 cells and within the spinal cord following chronic morphine treatment.Paeoniflorin directly suppresses morphine-induced microglial activation and thus results in potentiation of morphine acute analgesia and attenuation of morphine chronic antinociceptive tolerance.
- Comparative effects of pulmonary and parenteral Δ(9)-tetrahydrocannabinol exposure on extinction of opiate-induced conditioned aversion in rats. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Nov 15.
Evidence suggesting that the endogenous cannabinoid (eCB) system can be manipulated to facilitate or impair extinction of learned behaviours has important consequences for opiate withdrawal and abstinence. We demonstrated that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases eCB levels, facilitates extinction of a naloxone-precipitated morphine withdrawal-induced conditioned place aversion (CPA).The potential of the exogenous CB1 ligand, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), to facilitate extinction of this CPA was tested. Effects of both pulmonary and parenteral Δ(9)-THC exposure were evaluated using comparable doses previously determined.Rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered Δ(9)-THC-pulmonary (1, 5, 10 mg vapour inhalation) or parenteral (0.5, 1.0, 1.5 mg/kg intraperitoneal injection)-prior to each of 20 to 28 extinction/testing trials.Vapourized Δ(9)-THC facilitated extinction of the CPA in a dose- and time-dependent manner: 5 and 10 mg facilitated extinction compared to vehicle and 1 mg Δ(9)-THC. Injected Δ(9)-THC significantly impaired extinction only for the 1.0-mg/kg dose: it prolonged the CPA fourfold longer than the vehicle and 0.5- and 1.5-mg/kg doses.These data suggest that both dose and route of Δ(9)-THC administration have important consequences for its pharmacokinetic and behavioural effects; specifically, pulmonary exposure at higher doses facilitates, whereas pulmonary and parenteral exposure at lower doses impairs, rates of extinction learning for CPA. Pulmonary-administered Δ(9)-THC may prove beneficial for potentiation of extinction learning for aversive memories, such as those supporting drug-craving/seeking in opiate withdrawal syndrome, and other causes of conditioned aversions, such as illness and stress.
- The pharmacokinetics of oral oxycodone in patients after total gastric resection. [Journal Article]
- Eur Rev Med Pharmacol Sci 2014 Oct; 18(20):3126-33.
Oxycodone is a semi-synthetic opioid with a stronger analgesic effect than morphine and codeine. The efficacy of this opioid in the treatment of postoperative pain has been proved in different groups of patients. The drug has a favourable adverse reaction profile, which encourages doctors and patients to use it more and more widely. The drug is also used in the patients who underwent an abdominal surgery, e.g. stomach resection. Gastrectomy leads to pathophysiological changes within the gastrointestinal tract, which may cause changes in the drug absorption. In consequence this leads to a change in the pharmacokinetics and effect of the drug. The aim of the research was an analysis of the pharmacokinetics of oxycodone from prolonged release tablet in patients after total gastrectomy.The research was carried out on patients after gastrectomy with Roux-en-Y reconstruction. The patients (n=24; mean [SD] age, 67.6 [9.8] years; weight, 69.1 [13.6] kg; and BMI, 25.2 [4.0] kg/m2) received oxycodone in a prolonged release tablet in a single orally administered dose of 10 mg. Blood samples were collected within 12 h after the drug administration. The plasma concentrations of oxycodone and noroxycodone were measured with validated high-pressure liquid chromatography coupled with triple tandem mass spectrometery method.The main pharmacokinetic parameters for oxycodone in men (n = 14) and women (n = 10) were as follows: Cmax, 14.40 (3.76) and 11.54 (6.98) ng/ml (p = 0.2066); AUC0-∞, 157.87 (56.89) and 106.44 (61.31) ng´h/ml (p = 0.0460); tmax, 2.18 (0.58) and 2.15 (0.58) h (p = 0.8008), respectively.Total gastrectomy did not affect the pharmacokinetics of oxycodone administered in prolonged release tablets, but the exposure to the drug was significantly lower in women.