Paracetamol and asthma

Paracetamol (acetaminophen) is one of the over-the-counter analgesics that is used frequently for the self-management of some of the common disorders. There seems to be two types of relations between paracetamol and asthma - paracetamol intolerance leading to bronchospasm in analgesic-induced asthmatics; and the relation between asthma and the amount and frequency of consumption of paracetamol. Paracetamol is generally recommended as one of the safer analgesics in both analgesic tolerant and intolerant asthmatics, without the fear of severe bronchospasm that aspirin and other non-steroidal anti-inflammatory drugs can induce in these patients. However, Paracetamol is reported to cross-react with aspirin at a rate of approximately 20-30% in a dose-dependent way. Therefore, it should not be recommended to analgesic intolerant asthmatics, without performing oral provocation tests to prove its safety. The possible association between the amount and frequency of paracetamol consumption and the prevalence and degree of asthma as suggested by some of the recent surveys, needs to be investigated further.     

Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations.

BACKGROUND: Over-the-counter analgesics (OTCAs), principally paracetamol (acetaminophen)-containing compounds and NSAIDs, are commonly used medications. Guidelines for the use of these agents in patients with chronic liver disease (CLD) are not available, despite the possibility that such patients may be more susceptible to the effects of an adverse reaction. Notwithstanding the lack of guidelines for healthcare providers, patients are often counselled to modify their use of these drugs. Therefore, the primary aim of this study was to assess healthcare providers' recommendations on how OTCAs should be used by patients with CLD. METHODS: An 11-question web-based survey was distributed via email to healthcare providers participating in four healthcare networks in the US, to determine what recommendations they make to patients with cirrhosis (compensated and decompensated) and chronic hepatitis regarding the use of paracetamol and NSAIDs. Healthcare providers were also queried about the recommendations they make to patients with cirrhosis regarding pain control, and on the use of paracetamol for patients who consume alcohol daily. RESULTS: Overall, a 12% response rate was obtained. Internal medicine, family practice, paediatrics, and gastroenterology were the most represented practice types. Recommendations against the use of NSAIDs were significantly less common than recommendations against paracetamol use, in cases of both compensated and decompensated cirrhosis (p = 0.001). Non-gastroenterologists and non-primary care physicians were the least likely to recommend against NSAID use (p = 0.001), while gastroenterologists were the least likely to recommend against paracetamol in these patients (p = 0.001). It was the recommendation of most respondents that OTCAs should be avoided in patients with cirrhosis, and that paracetamol should be avoided or its dose reduced in the setting of daily alcohol use. CONCLUSIONS: Significant variability exists among healthcare providers on their recommendations for OTCA use in the setting of chronic liver disease. Non-gastroenterologists are more likely to recommend against the use of paracetamol than NSAIDs, and patients with chronic liver disease may be under-treated for pain.     

Update on sensitivity to nonsteroidal antiinflammatory drugs

Non steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications worldwide. These drugs are effective for the treatment of a wide spectrum of diseases: musculoskeletal disorders, headhache, fever, pain, and others. Their widespread use explains the very high incidence of intolerance; reactions range from asthma, rhinitis, to urticaria/angioedema, various skin eruptions and anaphylactic shock. The pathogenesis of intolerance is still unclear: immune-mediated reactions have been reported following the use of pyrazolone derivatives and, less commonly aspirin, anthranilic-acid derivatives and diclofenac. It has been suggested that NSAIDs may induce pseudoallergic reactions, while in case of bronchial asthma the inhibition of cyclooxigenase by NSAIDs has been proposed as a pathogenetic mechanism. The diagnosis of NSAIDs sensitivity can usually be established by history; in fact skin prick tests with NSAIDs have not been successful and no reliable in vitro tests are available. The only definitive diagnostic test is oral test dosing. To identify an alternative NSAIDs in a sensitive patient a tolerance test is performed. Here we review the current state of knowledge concerning NSAIDs sensitivity, including personal data to increase awareness on this issue.     

Concomitant NSAID use during antipsychotic treatment and risk of 2-year relapse – a population-based study of 16,253 incident patients with schizophrenia

Objective: Clinical trials have indicated antipsychotic effects of non-steroidal anti-inflammatory drugs (NSAIDs) among incident patients with schizophrenia. We aimed to study, in a population-based setting, whether concomitant use of NSAIDs or paracetamol, changed 2-year relapse risk for schizophrenia.

Methods: We identified all incident patients with schizophrenia in Denmark diagnosed 1996–2012 initiating antipsychotic treatment within the year after diagnosis. We calculated concomitant treatment intervals for antipsychotic and NSAID or paracetamol use. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for important covariates.

Main outcome measures: 2-year relapse, i.e. (re)-hospitalizations with schizophrenia.

Results: Among 16,235 incident patients with schizophrenia using antipsychotics, 1480 (9.1%) used NSAIDs and 767 (4.7%) paracetamol. Concomitant use of NSAIDs was associated with an increased risk of schizophrenia relapse (HRR = 1.21; 95%-CI = 1.11-1.31), particularly associated with acetylsalicylic acid and diclofenac. Concomitant use of paracetamol was not associated with schizophrenia relapse (HRR = 0.97; 95%-CI = 0.87-1.08). Subgroup analyses showed that individuals with somatic comorbidity and NSAID use had an increased relapse-risk, except for individuals with a prior hospital diagnosis for musculoskeletal disease and NSAID use who had a decreased relapse-risk (HRR = 0.82; 95%-CI = 0.71-0.94).

Conclusions: The increased relapse risk associated with concomitant NSAID use among incident patients with schizophrenia may indicate a potential impact of underlying somatic comorbidity.     

Adverse drug reactions to nonsteroidal anti-inflammatory drugs, COX-2 inhibitors and paracetamol in a paediatric hospital

AIMS: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in children has rapidly escalated over the last 5 years in Australia. This is primarily as a result of the availability of ibuprofen as an over-the-counter preparation. Several recent, significant adverse drug reactions (ADRs) to NSAIDs, at the Royal Children's Hospital (RCH) in Melbourne, Australia prompted review of all of the RCH reactions reported to these agents over 5 years. METHODS: The ADR programme documents both spontaneously reported ADRs and ADRs identified by discharge coding. For this study, reported reactions to aspirin, celecoxib, ibuprofen, indomethacin, naproxen, paracetamol and rofecoxib, for the previous 5-year period, were retrieved from the hospital ADR database. RESULTS: Nineteen reports of ADRs to NSAIDs and six to paracetamol, in patients aged from 4 months to 22 years (median 10 years) were identified. Reactions were predominantly rash (n = 10), gastrointestinal (n = 5) and respiratory (n = 4) side-effects. These included reports of haematemesis with both celecoxib and ibuprofen. One patient died of severe acute exacerbation of asthma following initiation of rofecoxib. CONCLUSION: NSAID exposures are a significant cause of morbidity in children. Both nonselective NSAIDs and the newer COX-2 inhibitors were associated with significant drug reactions. The overall severity of these ADRs highlights the need for vigilant surveillance of ADRs in paediatrics, including both established and newer agents.     

Acute treatment of migraines

Migraine is a prevalent and disabling brain disorder that costs billions of dollars annually in direct healthcare costs, and school and work absenteeism and presenteeism. The objective of acute treatment is a cost-effective, rapid restoration of functional ability, with minimal recurrence and adverse effects. The acute treatment of migraine includes specific drugs, which currently all have vasoconstrictive effects (dihydroergotamine and triptans), and nonspecific drugs that include paracetamol (acetaminophen), combination analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), dopamine antagonists, narcotics and corticosteroids. NSAIDs have both peripheral and central effects on reversing migraine, and so may represent the best alternative for patients who cannot use triptans and ergots due to vascular contraindications. Narcotics and habituating medications should be avoided in the acute treatment of migraine, as the risk for transformation to chronic daily headache is excessively high at a relatively infrequent rate of exposure.     

非甾体消炎药上消化道不良反应的防治

非甾体消炎药(non-steroid anti-inflammatory drugs,NSAIDs)可不同程度地引起胃肠道不良反应,是临床引起消化性溃疡和上消化道出血的常见药物,特别是在一些高危人群。此外还可增加患者的心血管事件如心肌梗死和卒中的危险,这使NSAIDs的药物选择和不良反应防治成为重要的临床和经济问题。NSAIDs的使用应选择恰当和必须的患者,并尽可能选用最小的剂量和最短的时间,并尽量避免多种NSAIDs联用。长期用药应限于那些不能耐受其他类型的镇痛药、并且能经常随访的患者。对NSAIDs消化道不良反应发生高危人群的用药应参照指南并积极采取预防措施。     

Understanding lactic acidosis in paracetamol (acetaminophen) poisoning

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.     

Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis

Celecoxib (Celebrex?) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties. In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400?mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis. Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs. Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800?mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs. Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.     

Postoperative pain control in children: a guide to drug choice

Postoperative pain in children can usually be well controlled with a combination of analgesics, including acetaminophen (paracetamol), NSAIDs, opioids, and local/regional anesthesia. Recent research has shown that the dosage of acetaminophen required to provide analgesia is higher than the traditional dosages used for the regulation of elevated body temperature. Rectal administration of acetaminophen gives a lower and more variable bioavailability compared with oral administration. There is growing experience with the use of NSAIDs in children and several studies have demonstrated the relatively strong analgesic potential of these drugs. Titration of opioids to analgesic effect, and the use of nurse- and patient-controlled continuous opioid infusions in children have gained widespread use and, with proper education and supervision, are considered excellent methods of pain control. Local peripheral and central blocks decrease the need for anesthetics during surgery and provide effective postoperative pain relief.     

Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks

Background  Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, but are not without risks.
Aim  To provide evidence-based management recommendations to help clinicians determine optimal long-term NSAID therapy and the need for gastroprotective strategies based on an assessment of both gastrointestinal (GI) and cardiovascular (CV) risks.
Methods  A multidisciplinary group of 21 voting participants revised and voted on the statements and the strength of evidence (assessed according to GRADE) at a consensus meeting.
Results  An algorithmic approach was developed to help manage patients who require long-term NSAID therapy. The use of low-dose acetylsalicylic acid in patients with high CV risk was assumed. For patients at low GI and CV risk, a traditional NSAID alone may be acceptable. For patients with low GI risk and high CV risk, full-dose naproxen may have a lower potential for CV risk than other NSAIDs. In patients with high GI and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor (PPI) may offer the best GI safety profile. When both GI and CV risks are high and NSAID therapy is absolutely necessary, risk should be prioritized. If the primary concern is GI risk, a COX-2 inhibitor plus a PPI is recommended; if CV risk, naproxen 500 mg b.d. plus a PPI would be preferred. NSAIDs should be used at the lowest effective dose for the shortest possible duration.
Conclusion  More large, long-term trials that examine clinical outcomes of complicated and symptomatic upper and lower GI ulcers are needed.     

Should NSAID/low‐dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing

Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti-inflammatory drugs - NSAIDs or selective COX-2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long-term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re-bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low-dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori-infected patients who require anti-inflammatory treatments.     

Exploring effects of different nonsteroidal antiinflammatory drugs on lipid peroxidation. Part II. 4-HNE profile

Non-steroidal anti-inflammatory drugs (NSAIDs) are common in alleviating pain, pyrexia and inflammation, in patients with rheumatoid arthritis and osteoarthritis. As these drugs are associated with high incidence of gastrointestinal ulceration, bleeding and kidney damage which may be linked with lipid peroxidation. our study was aimed to examine lipid peroxidation induction capacity of NSAIDs (diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide, celecoxib and indomethacin) by determining 4-hydroxy-2-nonenal (4-HNE) concentration as an index of lipid peroxidation and to see the suppressive potential of ascorbic acid on NSAID induced lipid peroxidation. The results suggest that diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide and celecoxib exerted mild antioxidant activity. Indomethacin exerted statistically significant increase in 4-HNE content, indicating statistically significant peroxidation activity. Ascorbic acid could significantly reduce indomethacin-induced lipid peroxidation.     

Back to the future: postoperative pain management beyond COX-2 inhibitors

In the aftermath of the heated dispute on COX-2 selective nonsteroidal anti-inflammatory drugs (NSAID) that led to the national and international withdrawal of several of the recently introduced coxibs, a balanced discussion of pros and cons for their short term use is warranted. Further debate and research has highlighted risks with both classical NSAIDs and coxibs when administered to patients with cardiovascular disease. For several decades discussion about indications, risks and contraindications for the perioperative use of classical NSAIDs has been ongoing. The COX debate has further added some uncertainty amongst practitioners. With a vast amount of research available on this topic, it should however be feasible to reach some consensus for the perioperative use of NSAIDs as well as for coxibs. This would ensure that the right patients take advantage of our present knowledge of NSAIDs as part of a multimodal and balanced perioperative analgesic regimen and at the same time that the patients at risk are not prescribed such drugs. Rational use of NSAIDs in the perioperative period would benefit a major group of patients who at present are deprived of such therapy due to unfounded fears of side effects and lack of knowledge among prescribers. This review highlights some of the aspects of short term (i.e. less than 5 days) perioperative use of NSAIDs.     

Patient satisfaction with arthritis medication

Patient derived information to support the long term use of non-steroidal anti-inflammatory drugs (NSAIDs) is lacking. In contrast, data detailing the adverse effects of individual NSAIDs is accumulating. We determined the importance of NSAIDs as therapy to 153 patients with osteoarthritis (age range 36 to 92), comparing results in elderly and younger patients. Around half of the patients reported moderate relief of symptoms, with a further quarter reporting good, or even excellent, relief. One half of patients aged 75 years or less, but only one fifth of patients aged over 75 years, recalled having been informed of the adverse effects of NSAIDs. A total of 59 per cent of patients reported having used simple analgesics, such as paracetamol, as first line therapy. As some patients are helped by them, we suggest that efforts should be directed towards increasing the first line use of simple analgesics in patients with osteoarthritis and towards increasing patient awareness of potential NSAID-related adverse effects.     

The management of chronic pain in important patient subgroups

Chronic pain is a major healthcare issue in Europe and globally, and inadequate or undertreated pain significantly reduces the ability of many patients to participate in ordinary daily activities, adversely affects their employment status and contributes to a substantial rate of depression and anxiety in patients with chronic pain. There is a broad distinction of chronic pain into chronic non-cancer pain and chronic cancer pain, and important subgroups of these include patients with rheumatic and/or orthopaedic diseases, pain syndromes caused by cancer itself and caused by cancer treatment. Despite comprising the majority of non-cancer pain in Europe, chronic non-cancer pain associated with rheumatic diseases and/or orthopaedic conditions is often inadequately managed. Although paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) play a continuing role in the treatment of chronic rheumatic diseases, accumulating evidence of potential toxicity with both traditional non-selective NSAIDs and selective cyclooxygenase 2 inhibitors has prompted a reassessment of their use. This has particular resonance for the elderly, who are more likely to have significant pain issues than younger patients and are at high risk of NSAID-related adverse events. The use of mild opioids, such as codeine and tramadol, and strong opioids, such as morphine, hydromorphone and oxycodone, may be appropriate where paracetamol and other non-opioid analgesics are ineffective in chronic non-cancer pain. Cancer pain, either related to the underlying disease or caused by cancer treatment, is also a common cause of chronic pain in the elderly. An understanding of individual needs is essential in providing adequate pain relief, which is a central goal of care in all patients with chronic pain.