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Journal: Journal of pain & palliative care pharmacotherapy


ABSTRACT Rheumatoid arthritis (RA) is a painful, debilitating disease characterized by inflammation of the joints, with the proliferation of the synovium and the progressive erosion of cartilage and bone. The treatment of RA is still unsatisfactory, but a number of powerful disease-modifying antirheumatic drugs have become available, such as methotrexate (MTX). Even in the current era of biological targeted therapies, MTX remains the initial preferred antirheumatic drug and is considered to be the gold standard for treatment of RA. The combination of its perceived efficacy, acceptable safety profile, and low cost, as well as decades of clinical experience, makes MTX the cornerstone of treatment for RA and the anchor drug in combination with various biological agents. In this review, the authors aim to summarize the research done in the field of drug delivery systems of MTX according to its routes of administration for treatment of RA. The last part of the review addresses combination therapy with MTX and future direction in the drug delivery of MTX. This review also provides the reader with a general overview of RA and its therapeutic strategies with respect of MTX, which may bring uniformity in medical practice for effective management of RA.

Concepts: Methotrexate, Pharmacology, Osteoarthritis, Therapy, Drugs, Disease-modifying antirheumatic drug, Medicine, Rheumatoid arthritis


ABSTRACT Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a “main stream” pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC0→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

Concepts: Medicine, Distribution, Pharmacokinetics, Tetrahydrocannabinol, Cannabis, Neuropathic pain, Medical cannabis, Pharmacology


Harmful and nonmedical use of prescription opioids has increased precipitously in the United States and some other countries in recent years, but not everywhere around the world. Addressing this problem requires attention to scientific data and to objective and balanced consideration of factors driving the problems. Unfortunately, the situation has been blurred by some politicians, health professionals, and the media by their using inadequate concepts, misrepresenting and exaggerating facts, and demonizing pain patients. In this article, we analyze what has occurred and present what we believe to be a balanced view of the problems. We advocate comprehensive drug control policies implemented in a way to reduce harmful use and diversion problems balancing the public health benefits and risks of opioid medications. We make recommendations for responsible prescribing, including implementing the World Health Organization (WHO) policy guidelines and similar United Nations Office of Drug Control (UNODC), which we believe can contribute measurably to the prevention of diversion of prescription opioids while ensuring patient access to the most appropriate medicines. Measures to reduce the risks of nonmedical use of opioid medicines should be based to the greatest extent possible on accurate evaluation of the mechanisms leading to such use, including diversion activities.

Concepts: Pharmaceutical drug, Public health, Implementation, Pharmacology, Drug, United States, Opioid, World Health Organization


The potential association between serotonin syndrome and tapentadol is not well described in the literature. This study aimed to review the literature and identify methodological issues that could lead to inaccurately reported rates of serotonin syndrome associated with tapentadol use. A systematic review of English articles using MEDLINE, Cochrane Controlled Trials Register, and Scopus was performed. Additional studies were identified by cross-referencing article bibliographies. Original research that examined the safety of tapentadol in patients with nonconfounding indications were examined. In total, 22 studies met inclusion criteria. There were 13 randomized clinical trials, 7 open-label trials, and 2 observational studies. All studies either did not mention whether serotonergic medication use was prohibited or disallowed use. Frequently reported adverse events were nausea, diarrhea, constipation, fatigue, vomiting, and somnolence. No studies reported serotonin syndrome development. No included trials differentiated between the development of adverse events in patients taking serotonergic drugs and those who were not. This differentiation is necessary to evaluate the increased risk of adverse events in patients prescribed tapentadol concomitantly with other serotonergic medications. Therefore, the current tapentadol literature has important limitations that prevent the adequate characterization of the potential association between tapentadol and serotonin syndrome.

Concepts: Scientific method, Adverse event, Serotonin, Randomized controlled trial, Pharmaceutical industry, Clinical research, Pharmacology, Clinical trial


Urinary retention is a common problem at end-of-life that may be a result of medications used to control other symptoms. To determine whether use of retention-causing drugs was associated with catheterization for urinary retention among palliative care unit (PCU) patients, the authors reviewed charts of 91 consecutively admitted patients to a hospital-based PCU. Utilization of eight classes of retention-causing medications (opioids, antidopaminergics, benzodiazepines, anticholinergics, antidepressants, calcium channel antagonists, nonsteroidal anti-inflammatory drugs [NSAIDs], and H1 histamine antagonists) was compared between those catheterized for urinary retention (n = 34) and those never catheterized (n = 31). All patients used medication from more than one class of retention-causing medication. A statistically significant association with urinary retention occurred for antidopaminergic medications, but not other drug classes. The total number of classes of retention-causing medications was not associated with catheterization. These findings question whether urinary retention need hinder medication use for symptom management at end-of-life. Tapering of antidopaminergic medications, compared with other drug classes studied, may be more likely to resolve retention.

Concepts: Paracetamol, Non-steroidal anti-inflammatory drug


Prescription opioids are among the most effective analgesics to treat moderate to severe pain; however, little is known about the use of prescription opioids in children, particularly those receiving an extended-release formulation for the treatment of chronic pain. In this retrospective study, the authors determined the prevalence of prescription opioid use among 7-17-year-old children and associated comorbid health conditions from 2010 to 2013 using Truven Health MarketScan (MarketScan) and Optum Clinformatics DataMart (Optum). The primary end points were prevalence of using any prescription opioids, using only prescription short-acting opioids (SAOs), and at least one prescription of a long-acting opioid (LAO). The prevalence of prescription opioid use among children is non-negligible and has been trending downwards: 6.90% in 2010 and 5.93% in 2013 using MarketScan and a similar trend using Optum: 5.47% in 2010 and 4.51% in 2013. Very few children had claims for LAOs, with only 0.04% (4979 children) in MarketScan and 0.03% (1117 children) in Optum. Given the very small number of children, primarily in the 12-17 age group, who are prescribed LAOs, there is a need to focus on a better understanding of the patterns of SAO use in children.

Concepts: Heroin, Hydrocodone, Buprenorphine, Morphine, Ketamine, Opioid, Pain


Patients receiving palliative care and those at the end of life are known to be susceptible to medical errors. Errors related to medications are the most avoidable cause of patient harm. This retrospective study examined reported anonymized medication safety incidents, related to physician errors, assessed by the risk committee in a specialist palliative care unit over a 3-year time period. The aim of the study was to describe medication errors, with specific attention paid to what type of errors occurred and when these errors happened. Of the 218 reported medication safety incidents 28% (n = 62) were related to doctor prescribing. The data showed that there was a wide variation per year in the numbers of reported medication safety incidents. Medication prescribing errors were the most common error, followed by medication omissions. Medication safety incidents are at least in part dependent on staff reporting. Fostering a culture of openness that is blame free is crucial to medication error reporting. Formal reporting may help to increase patient safety and forms an essential element in the clinical governance and risk management of an institution.

Concepts: Hospice, Hospital accreditation, Iatrogenesis, Patient Safety and Quality Improvement Act, Medical error, Medicine, Palliative care, Patient safety


The Cochrane Library of Systematic Reviews is now only published monthly online ( ). The methods for searching have changed and are in flux. This report attempted to identify all relevant reviews published in the last 3 months to March 30, 2017. The current version contains 7243 complete reviews and 2544 protocols for reviews in production. In addition, there are citations of 1,036,153 randomized controlled trials (first time passing the million mark) and 15,700 cited papers in the Cochrane Methodology Register. The Health Technology Assessment database contains some 17,000 citations. Six reviews have been identified that have potential relevance for practitioners in pain and palliative medicine. The impact factor of the Cochrane Library stands at 6.1. Readers are encouraged to access the full report for any articles of interest, as only a brief commentary is provided.

Concepts: Cochrane Library, Systematic review, Randomized controlled trial, Evidence-based medicine


Delirium is a common problem in terminally ill patients that is associated with significant distress and, hence, considered a palliative care emergency. The three subtypes of delirium are hyperactive, hypoactive, and mixed, depending on the level of psychomotor activity and arousal disturbance. When agitated delirium becomes refractory in the setting of imminent dying, the agitation may be so severe that palliative sedation (PS) is required. Palliative sedation involves the administration of sedative medications with the purpose of reducing level of consciousness for patients with refractory suffering in the setting of a terminal illness. Propofol is a sedative that has a short duration of action and a very rapid onset. These characteristics make it relatively easy to titrate. Reported doses range from 50 to 70 mg per hour. The authors present a case of antipsychotic-resistant agitated delirium treated with a propofol intravenous infusion.

Concepts: Terminal illness, Illness, Hospice, Death, Medical terms, Terminal sedation, Palliative care, Palliative medicine


A 44-year-old Caucasian woman presented with a history of empirical treatment with 20 pain and psychotropic medications, as well as dual comorbidity of intractable pain and depression. A multiple gain-of-function profile in the CYP450 family of cytochrome P450 (CYP450) drug metabolism isoenzymes was discovered. The patient was a homozygote of suprafunctional alleles for both CYP2D6 ((*)35/(*)35) and CYP2C19 ((*)17/(*)17) genes and functional alleles for CYP2C9 ((*)1/(*)1), which account for aggregate drug metabolism function at the upper 1% of the population. The patient improved clinically with discontinuation of psychotropics and pain medications that were substrates of CYP2D6 and/or CYP2C19, suggesting that much of her symptomatology was drug induced. Combinatorial genotyping of CYP450 genes is diagnostically useful in individuals with histories of multiple side effects or drug resistance, which could be avoided by genetically informed therapeutics in behavioral health.

Concepts: Xenobiotic, CYP2C19, CYP2C9, CYP2D6, Psychoactive drug, Genetics, Metabolism, Cytochrome P450