Analgesic treatments in people with dementia - how safe are they? A systematic review

Introduction: People with dementia may be unable to verbally express pain and suffer from untreated pain. Use of analgesics in people with dementia has increased during the last decade, in particular opioid analgesics with high potential for adverse effects.

Areas covered: This article presents a systematic review of the current evidence for safety and tolerability of analgesic drugs from randomized controlled trials in people with dementia. Relevant trials were identified by a literature search in the EMBASE, MEDLINE, and Cochrane databases from inception to November 2018. The search included the main terms ‘dementia’ and ‘analgesic’ or their subterms, and was filtered to limit results to clinical trials.

Expert opinion: Although pain treatment is increasingly recognized as an important clinical issue in people with advanced dementia, there is currently a lack of evidence to support safety evaluations of commonly used analgesics in this group. To inform treatment decisions and enable care providers to appropriately monitor patients at risk of adverse effects, it is necessary to conduct well-designed clinical trials to investigate the relative efficacy and safety of analgesics in people with dementia, with particular emphasis on harmful effects of long-term opioid use as well as short-term use of nonsteroidal anti-inflammatory drugs.     

Extrapolation for a pharmacokinetic model for acetaminophen from adults to neonates: A Latin Hypercube Sampling analysis

Physiological and drug-specific parameters need to be adjusted when extrapolating a pharmacokinetic (PK) model from adults to neonates, so as to reproduce the time profiles of the studied drug(s) consistent with clinical, in vivo data or in vitro cell line measurements. In this paper we present a parameter analysis method, i.e. the Latin Hypercube Sampling (LHS) method for an acetaminophen (APAP) PK model. The original model consists of two compartments (the blood and the urine) with Michaelis-Menten kinetic parameters determined for APAP and its metabolites. The physiological parameters are scaled through allometric laws from adults to neonates, and APAP-specific parameters are adjusted for enzymatic maturational changes. The LHS method is used to statistically investigate the interplay between these parameters. The results for the extrapolated APAP model are consistent with published APAP PK data in neonates. We found the sulphation clearance parameter played a crucial role in the neonatal PK model, but its influence was weakened if the volume of distribution parameters were included. We suggest that this kind of in silico experiment could be valuable as the first step in PK model extrapolation between different ages.     

Effect of combination of preoperative ibuprofen/acetaminophen on the success of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis

Introduction

The purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of the administration of the combination of preoperative ibuprofen/acetaminophen on the success of the inferior alveolar nerve (IAN) block in patients with symptomatic irreversible pulpitis.

Methods

One hundred endodontic emergency patients in moderate to severe pain diagnosed with irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either a combination of 800 mg ibuprofen and 1000 mg acetaminophen or placebo 45 minutes before the administration of a conventional IAN block. Access was begun 15 minutes after completion of the IAN block, and all patients had profound lip numbness. Success was defined as no or mild pain (visual analog scale recordings) on access or initial instrumentation.

Results and Conclusions

The success rate for the IAN block was 32% for the combination ibuprofen/acetaminophen group and 24% for the placebo, with no significant difference (P = .37) between the 2 groups. For mandibular posterior teeth, a combination dose of 800 mg ibuprofen and 1000 mg acetaminophen given 45 minutes before administration of the IAN block did not result in a statistically significant increase in anesthetic success in patients with symptomatic irreversible pulpitis.     

Does Acetaminophen/Hydrocodone Affect Cold Pulpal Testing in Patients with Symptomatic Irreversible Pulpitis? A Prospective,Randomized, Double-blind,Placebo-controlled Study

Introduction

The purpose of this prospective randomized, double-blind, placebo-controlled study was to determine the effects of a combination dose of 1000 mg acetaminophen/10 mg hydrocodone on cold pulpal testing in patients experiencing symptomatic irreversible pulpitis.

Methods

One hundred emergency patients in moderate to severe pain diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either a combination of 1000 mg acetaminophen/10 hydrocodone or placebo. Cold testing with Endo-Ice (1,1,1,2 tetrafluoroethane; Hygenic Corp, Akron, OH) was performed at baseline and every 10 minutes for 60 minutes. Pain to cold testing was recorded by the patient using a Heft-Parker visual analog scale. Patients' reaction to the cold application was also rated.

Results

Cold testing at baseline and at 10 minutes resulted in severe pain for both the acetaminophen/hydrocodone and placebo groups. Although pain ratings decreased from 20–60 minutes, the ratings still resulted in moderate pain. Patient reaction to cold testing showed that 56%–62% had a severe reaction. Although the reactions decreased in severity over the 60 minutes, 20%–34% still had severe reactions at 60 minutes. Regarding pain and patients' reactions to cold testing, there were no significant differences between the combination acetaminophen/hydrocodone and placebo groups at any time period.

Conclusions

A combination dose of 1000 mg of acetaminophen/10 mg of hydrocodone did not statistically affect cold pulpal testing in patients presenting with symptomatic irreversible pulpitis. Patients experienced moderate to severe pain and reactions to cold testing.     

Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants

ObjectivesAcetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury.Design and methodRats were divided into nine groups; control group, APAP intoxicated group (1000 mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, α-LA, CR plus TQ, TQ plus α-LA, or CR plus α-LA. The first dose of the aforementioned antioxidants was given 24 h before APAP, and then the second dose was given 2 h after APAP, whereas the last dose was given 10 h after administration of APAP.ResultsTreatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree.ConclusionThe combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment.     

High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP''s anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP''s liver toxicity, did not rescue cells from AAP''s anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP''s molecular scaffold.     

Acetaminophen toxicity up-regulates MRP2 expression in the liver of cats: an old story with new vision

This study was conducted to clarify the role of efflux transporter MRP₂ in acetaminophen-induced hepatotoxicity in cats. Sixteen mixed bred male cats and four liver samples from mixed breed male dogs were used. The cats were assigned into four groups (n?=?4), received saline and 2, 10 and 50?mg/kg doses of acetaminophen orally for 14 days. Unlike the intact dogs, the MRP₂ was not detectable in control cats. MRP₂ at mRNA level was expressed in the liver of cats, which received the medium and high doses. Data suggest that the MRP₂ expression may involve in the acetaminophen-induced hepatotoxicity in cats.