Treatment of chronic pain in pediatric rheumatic disease

Pain in children with rheumatic disease is common, and is most often caused by arthritis. Despite the widespread use of effective new biologic agents, pain continues to be a problem in these patients, and it greatly impairs their daily functioning and quality of life. The pathogenesis of pain in children with rheumatic diseases is multifactorial, and disease treatment alone is often not enough to alleviate it. No standard of care or detailed algorithm for managing pain in these patients exists. Specific pain treatments often include acetaminophen, NSAIDs and medications that treat arthritis, such as methotrexate and etanercept. Other approaches should include nonpharmacologic interventions, for example exercise and cognitive-behavioral therapy, as well as the use of analgesics such as opioids in patients whose pain is refractory to standard therapies. The use of systemic corticosteroids to treat pain in children with arthritis should be avoided.     

Pain management today—what have we learned?

Pain is a leading cause of morbidity worldwide, with published data showing its prevalence as high as 50% for chronic pain in the European population. This prevalence is likely to continue to rise, particularly in elderly people with comorbid conditions and complex aetiologies of pain. There is thus a rapidly growing demand for safe and effective pain management. Management of mild-to-moderate pain has traditionally been based upon the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the synthetic non-opioid analgesic paracetamol (acetaminophen), the latter of which acts centrally, inhibiting brain cyclo-oxygenase (COX) and nitric oxide synthase. Both the NSAIDs and paracetamol are effective for mild-to-moderate pain and are widely recommended and used. However, NSAIDs may not be tolerated due to gastrointestinal (GI) symptoms and can result in potentially fatal peptic ulceration and bleeding. Selective COX-2 inhibitors were developed to reduce the GI side effects and complications, but large-scale studies have highlighted another serious potential effect of anti-inflammatory drugs: cardiovascular events. Both the European Medicines Agency (EMEA) and the Food and Drugs Administration (FDA) in the US have issued advice to apply cautions and restrictions when prescribing COX-2 inhibitors, particularly for patients at increased cardiovascular risk and for long-term use. The FDA also applied cardiovascular warnings with regard to nonselective NSAIDs. Both the EMEA and the FDA have recommended using the lowest effective dose for the shortest duration. These concerns and warnings have left physicians seeking safe alternatives to anti-inflammatory drugs for both short- and long-term uses in many patients. These developments have generated a climate of uncertainty in the absence of official guidance on the selection of alternative analgesic regimens. Amongst the possible strategies, combinations of drugs that provide analgesic efficacy at reduced individual doses may confer the optimal risk–benefit ratio for pain management in the long term or in patients at increased cardiovascular risk. Weak opioids devoid of serious organ-damaging effects combined with paracetamol may well be safer for long-term therapy. Fixed-dose combinations of paracetamol with weak opioids, such as codeine, dextropropoxyphene or tramadol are currently available. Paracetamol plus tramadol is an effective and safe multimodal analgesic regimen for the management of both acute and chronic moderate-to-severe pain. Re-evaluating the role of weak opioids, such as tramadol, and combinations in pain management may prove a valuable option for prescribers seeking alternatives to anti-inflammatory drugs.     

Treatment of osteoarthritis with acetaminophen: Efficacy, safety, and comparison with nonsteroidal anti-inflammatory drugs

Osteoarthritis represents a major public health problem with limited effective treatment. Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used to alleviate symptoms such as pain and stiffness. However, these drugs are associated with an increased risk for the development of adverse sequelae, including serious upper gastrointestinal side effects such as symptomatic ulcers, perforation, obstruction, and gastrointestinal bleeding. The simple analgesic acetaminophen has been found to be effective in alleviating pain in patients with osteoarthritis in a placebo-controlled trial, and several trials have evaluated its efficacy and safety compared with NSAIDs. This article reviews data regarding the efficacy and safety of acetaminophen in the treatment of osteoarthritis from randomized, controlled, clinical trials, focusing on studies that compared acetaminophen with NSAIDs. In addition, literature on physician and patient preferences in this area are examined. In summary, judicious use of analgesic agents as pharmacologic therapy in patients with osteoarthritis will achieve satisfactory pain relief in most cases. Acetaminophen merits a trial as initial terapy in patients with mild to moderate pain, based on cost-effectiveness and safety profile.     

Pain management today - what have we learned?

Pain is a leading cause of morbidity worldwide, with published data showing its prevalence as high as 50% for chronic pain in the European population. This prevalence is likely to continue to rise, particularly in elderly people with comorbid conditions and complex aetiologies of pain. There is thus a rapidly growing demand for safe and effective pain management. Management of mild-to-moderate pain has traditionally been based upon the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the synthetic non-opioid analgesic paracetamol (acetaminophen), the latter of which acts centrally, inhibiting brain cyclo-oxygenase (COX) and nitric oxide synthase. Both the NSAIDs and paracetamol are effective for mild-to-moderate pain and are widely recommended and used. However, NSAIDs may not be tolerated due to gastrointestinal (GI) symptoms and can result in potentially fatal peptic ulceration and bleeding. Selective COX-2 inhibitors were developed to reduce the GI side effects and complications, but large-scale studies have highlighted another serious potential effect of anti-inflammatory drugs: cardiovascular events. Both the European Medicines Agency (EMEA) and the Food and Drugs Administration (FDA) in the US have issued advice to apply cautions and restrictions when prescribing COX-2 inhibitors, particularly for patients at increased cardiovascular risk and for long-term use. The FDA also applied cardiovascular warnings with regard to nonselective NSAIDs. Both the EMEA and the FDA have recommended using the lowest effective dose for the shortest duration. These concerns and warnings have left physicians seeking safe alternatives to anti-inflammatory drugs for both short- and long-term uses in many patients. These developments have generated a climate of uncertainty in the absence of official guidance on the selection of alternative analgesic regimens. Amongst the possible strategies, combinations of drugs that provide analgesic efficacy at reduced individual doses may confer the optimal risk-benefit ratio for pain management in the long term or in patients at increased cardiovascular risk. Weak opioids devoid of serious organ-damaging effects combined with paracetamol may well be safer for long-term therapy. Fixed-dose combinations of paracetamol with weak opioids, such as codeine, dextropropoxyphene or tramadol are currently available. Paracetamol plus tramadol is an effective and safe multimodal analgesic regimen for the management of both acute and chronic moderate-to-severe pain. Re-evaluating the role of weak opioids, such as tramadol, and combinations in pain management may prove a valuable option for prescribers seeking alternatives to anti-inflammatory drugs.     

Frequency of analgesic use and risk of hypertension in younger women

BACKGROUND: In addition to their antipyretic, anti-inflammatory, and pain-relieving effects, analgesics may interfere with blood pressure regulation. However, little prospective information is available on the association between analgesic use and the risk of hypertension. METHODS: We performed a prospective study of 80 020 women aged 31 to 50 years who participated in the Nurses' Health Study II and had no previous history of hypertension. Frequency of use (in days per month) of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was collected by mailed questionnaire in 1995. Incident cases of physician-diagnosed hypertension were identified by self-report on the 1997 biennial questionnaire. RESULTS: During 164 090 person-years of follow-up, 1650 incident cases of hypertension were identified. At least 1 d/mo, 51.2% of the cohort used aspirin, 76.7% used NSAIDs, and 72.5% used acetaminophen. After adjusting for age, all 3 classes of analgesics were associated with an increased risk of incident hypertension (P<.001 for trend). After further adjustment for all 3 analgesics and other potential risk factors, only NSAIDs and acetaminophen (P<.001 for trend for both) were significantly associated with risk of hypertension. Compared with nonusers, the relative risk of hypertension for women taking NSAIDs 22 d/mo or more was 1.86 (95% confidence interval, 1.51-2.28) and for those taking acetaminophen 22 d/mo or more was 2.00 (95% confidence interval, 1.52-2.62). CONCLUSIONS: Use of NSAIDs and use of acetaminophen were significantly associated with increased risk of hypertension, but aspirin use was not. A substantial proportion of hypertension in the United States, and the associated morbidity and mortality, may be due to the use of these medications.     

Nonnarcotic analgesic use and the risk of hypertension in US women

Acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed. Each is theoretically capable of elevating blood pressure by altering prostaglandin homeostasis; however, there is little prospective information on the relation between these agents and physician-diagnosed hypertension. We examined the association between the use of aspirin, acetaminophen, or NSAIDs and incident hypertension in a prospective cohort study of 51 630 women 44 to 69 years of age in 1990 who had no history of hypertension or chronic renal insufficiency. Analgesic use was assessed in 1990 by a mailed questionnaire, and the women were followed for 8 years. The primary outcome was physician-diagnosed hypertension reported on a follow-up biennial questionnaire. During 381 078 person-years of follow-up, 10 579 incident cases of hypertension were identified. Compared with nonusers, women who used aspirin or acetaminophen at least 1 day per month or NSAIDs 5 or more days per month were at a significantly higher risk for development of hypertension. After adjusting for potential confounders, the odds ratios for women in the highest frequency of use category (> or =22 days per month) compared with no use were as follows: aspirin, 1.21 (95% CI, 1.13 to 1.30); acetaminophen, 1.20 (1.08 to 1.33); and NSAIDs, 1.35 (1.25 to 1.46). For each analgesic type, there was a significant trend toward an increased risk of incident hypertension with increasing frequency of use (P<0.001). Given the observed odds ratios, biologic plausibility, and the sizeable population at risk, health professionals should consider potential hypertensive effects of aspirin, acetaminophen, and NSAIDs when counseling their patients about the use of nonnarcotic analgesics.     

Pain in children with rheumatic diseases

Pain is common in rheumatic diseases in children. Despite recent advances in arthritis treatment, pain continues to be a problem impacting daily functioning and quality of life, and no standard of care for pain management exists. The pathogenesis of pain in children with rheumatic diseases is multifactorial, and treatment of the disease alone may not be enough. Current pain treatment often includes acetaminophen, nonsteroidal anti-inflammatory drugs, and medications that treat arthritis such as methotrexate and etanercept. Nonpharmacologic interventions, such as exercise and cognitive-behavioral therapy as well as the use of analgesics such as opioids in patients whose pain is refractory to standard therapies, should also be considered. The use of systemic corticosteroids to treat pain in children with arthritis should be avoided. Idiopathic pain may coexist in children with rheumatic disease, but treatment of idiopathic pain is different than that of pain due to inflammatory disorders.     

Managing chronic pain in adults with haemophilia: current status and call to action

Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated bleeding into joints. Unlike other conditions (e.g. osteoarthritis, rheumatoid arthritis, sickle cell disease), there are limited data on pain management in haemophilia. Management of arthritic individuals and those with sickle cell disease relies heavily on administration of acetaminophen, non‐steroidal anti‐inflammatory drugs (NSAIDs) and opioid analgesics. In haemophilia, acetaminophen often has limited efficacy at therapeutic doses, offering a narrow dosing range in those with liver disease due to chronic hepatitis C. NSAIDs can effectively manage pain in patients with haemophilia, but these agents are potentially associated with a significant risk of precipitating or exacerbating bleeding complications in an already coagulopathic population. Opioids have proven effective in osteoarthritis and sickle cell disease, but outcomes data in those with haemophilia are virtually non‐existent. Patients with haemophilia are at least as vulnerable as other chronic pain populations to opioid‐related adverse events and to developing abusive behaviours and addiction. Despite pain management strategies for patients with haemophilia being far from optimal, the predominant precept of haemophilia management still applies. As such, it is critically important to aggressively reverse or prevent acute symptomatic bleeding in a timely and effective manner to at least minimize pain and progressive joint damage. This review should serve as a call to action to prioritize pain management in haemophilia care and spur interest in the development, improvement and standardization of tools to assess and manage acute and chronic pain in haemophilia.     

Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia

OBJECTIVE: Because there is controversy regarding the efficacy of acetaminophen in rheumatic diseases and because apparently safer nonsteroidal antiinflammatory drugs (NSAIDs) are being produced, we surveyed rheumatic disease patients about their preferences for these agents to determine the degree to which one type of therapeutic agent is preferred over the other. METHODS: In 1998, we surveyed by mailed questionnaire 1,799 patients with osteoarthritis (OA), rheumatoid arthritis, or fibromyalgia who were participating in a long-term outcome study. Patients who had taken acetaminophen rated the effectiveness of acetaminophen, compared its effectiveness with that of NSAIDs, and then rated their overall satisfaction with acetaminophen compared with NSAIDs when both effectiveness and side effects were considered. RESULTS: Two-thirds of study participants had taken acetaminophen. About 37% of patients who had taken acetaminophen found it to be moderately or very effective and about 63% indicated that it was not effective or was only slightly effective. One-fourth of the patients found acetaminophen and NSAIDs to be equally effective, but >60% found acetaminophen to be much less effective or somewhat less effective. About 12% preferred acetaminophen to NSAIDs. When both effectiveness and side effects were considered together, 25% of the patients had no preference, 60% preferred NSAIDs, and 14% preferred acetaminophen. CONCLUSION: There was a considerable and statistically significant preference for NSAIDs compared with acetaminophen among the 3 groups of rheumatic disease patients. Although this preference decreased slightly with age and was less pronounced in OA patients, the preference was noted among all categories of patients and was not altered by disease severity. If safety and cost are not issues, there would hardly ever be a reason to recommend acetaminophen over NSAIDs, since patients generally preferred NSAIDs and fewer than 14% preferred acetaminophen. If safety and costs are issues, then the recommendation of the American College Rheumatology that acetaminophen be tried first seems correct, since 38.2% found acetaminophen to be as effective or more effective than NSAIDs.     

Pharmacological therapy of osteoarthritis

In 2000, both the American College of Rheumatology (ACR) and the European League of Associations of Rheumatology (EULAR) published recommendations for the use of pharmacological therapy in the treatment of patients with lower limb osteoarthritis. These recommendations are based on the level of evidence observed in systematic reviews and/or meta-analyses of published randomized controlled trials as well as expert opinion. Acetaminophen (paracetamol) is considered as first-line oral therapy for symptomatic lower limb osteoarthritis with mild to moderate pain because it is more efficacious than placebo and is generally considered to be safe and well tolerated. Data obtained in recent trials and the results of a meta-analysis, however, show that acetaminophen is not as efficacious as non-steroidal anti-inflammatory drugs (NSAIDs) for pain at rest and pain on motion. Furthermore, data from a recent epidemiological study suggest that use of high-dose acetaminophen (>2 g/day) may convey the same magnitude of increased risk for serious upper gastrointestinal adverse events as NSAIDs.NSAIDs have demonstrated efficacy superior to placebo in patients with osteoarthritis. The newer cyclo-oxygenase (COX)-2-specific inhibitors (coxibs) have comparable efficacy to traditional dual inhibitor NSAIDs and have demonstrated a better gastrointestinal safety profile. Thus, for patients who have severe pain and/or signs of inflammation or who have failed to respond to acetaminophen, the use of a coxib should be considered, especially if the patient is at increased risk for serious upper gastrointestinal adverse events from a traditional NSAID.Compounds different from pure analgesics and NSAIDs are also used for the management of patients with osteoarthritis. Recent clinical trials have demonstrated statistically significant efficacy of such compounds (e.g. chondroitin sulphate, diacerhein, glucosamine sulphate) with the following characteristics: (1) the effect size seems to be of slightly lower magnitude than that seen for NSAIDs; (2) the onset of action is delayed for approximately 4 to 6 weeks; and (3) the symptomatic effect is maintained after stopping the treatment for periods of 4 to 8 weeks.The methodology for evaluating the possible structure-modifying effect of drugs has dramatically improved during the past decade. Two agents have demonstrated a beneficial structural effect: glucosamine sulphate in osteoarthritis of the knee, and diacerhein in osteoarthritis of the hip. The clinical relevance of such an effect needs to be further evaluated in long-term outcome studies.     

Persistent nonmalignant pain and analgesic prescribing patterns in elderly nursing home residents

OBJECTIVES: To determine the prevalence of analgesics used, their prescribing patterns, and associations with particular diagnoses and medications in patients with persistent pain. DESIGN: Cross-sectional study. SETTING: Nursing homes from 10 U.S. states. PARTICIPANTS: A total of 21,380 nursing home residents aged 65 and older with persistent pain. MEASUREMENTS: Minimum Data Set (MDS) assessments on pain, analgesics, cognitive, functional, and emotional status were summarized. Logistic regression models identified diagnoses associated with different analgesic classes. RESULTS: Persistent pain as determined using the MDS was identified in 49% of residents with an average age of 83; 83% were female. Persistent pain was prevalent in patients with a history of fractures (62.9%) or surgery (63.6%) in the past 6 months. One-quarter received no analgesics. The most common analgesics were acetaminophen (37.2%), propoxyphene (18.2%), hydrocodone (6.8%), and tramadol (5.4%). Only 46.9% of all analgesics were given as standing doses. Acetaminophen was usually prescribed as needed (65.6%), at doses less than 1,300 mg per day. Nonsteroidal antiinflammatory drugs (NSAIDs) were prescribed as a standing dose more than 70% of the time, and one-third of NSAIDs were prescribed at high doses. CONCLUSION: In nursing home residents, persistent pain is highly prevalent, there is suboptimal compliance with geriatric prescribing recommendations, and acute pain may be an important contributing source of persistent pain. More effective provider education and research is needed to determine whether treatment of acute pain could prevent persistent pain.     

The role of intra-articular hyaluronan (Sinovial?) in the treatment of osteoarthritis

Osteoarthritis (OA) leads to significant pain and disability. For pain relief, a tailored approach using non-pharmacological and pharmacological therapies is recommended. If adequate symptom relief is not achieved with acetaminophen, other pharmacological options include non-steroidal anti-inflammatory drugs (NSAIDs), topical analgesics, intra-articular corticosteroids and intra-articular hyaluronic acid (HA) viscosupplementation. Most of these therapies generally do not improve functional ability or quality of life or are associated with tolerability concerns. In OA patients, concentration and molecular weight (MW) of HA are reduced, diminishing elastoviscosity of the synovial fluid, joint lubrication and shock absorbancy, and possibly anti-inflammatory, analgesic and chondroprotective effects. In knee OA, viscosupplementation with 3–5 weekly intra-articular HA injections diminishes pain and improves disability, generally within 1 week and for up to 3–6 months and is well tolerated. HAs have comparable efficacy as NSAIDs, with less gastrointestinal adverse events, and compared with intra-articular corticosteroids, benefits last generally longer. High MW hylans provide comparable benefits versus HA, albeit with an increased risk of immunogenic adverse events. In mild-to-moderate hip OA, intra-articular injection of HA moderately improved pain and function, generally for up to 3 months with no serious adverse events. Efficacy in other joints is being evaluated. Viscosupplementation with intra-articular Sinovial^? (other trade names: Yaral^?, Intragel^?) injections (an HA of low-medium MW) relieves pain and improves function in OA of the knee, and other joints including the carpometacarpal joint of the thumb and the shoulder. HA viscosupplementation, including use of Sinovial^?, is a valuable treatment approach for OA patients, if other therapies are contraindicated or have failed.     

A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain

Analgesic therapy that combines individual agents with different mechanisms of action has potential advantages for the management of mild-to-moderate pain in the outpatient setting. Theoretically, this approach can lead to greater efficacy and fewer adverse events. While the precise mechanism of action for the analgesic effect of acetaminophen remains uncertain, accumulating evidence suggests that its activity resides primarily in the central nervous system. In contrast, the site of action for the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is predominantly peripheral, within injured or inflamed tissue. Several controlled clinical studies among patients with musculoskeletal conditions, dental pain, or postoperative pain have shown that combinations of acetaminophen and NSAIDs provide additive pain-relieving activity, thereby leading to dose-sparing effects and improved safety. Further studies are warranted to determine the clinical utility and safety of acetaminophen/NSAID combinations as analgesic therapy for common conditions associated with mild-to-moderate pain.     

Analgesic Use and the Risk of Hearing Loss in Men

Background

Hearing loss is a common sensory disorder, yet prospective data on potentially modifiable risk factors are limited. Regularly used analgesics, the most commonly used drugs in the US, may be ototoxic and contribute to hearing loss.

Methods

We examined the independent association between self-reported professionally diagnosed hearing loss and regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen in 26,917 men aged 40-74 years at baseline in 1986. Study participants completed detailed questionnaires at baseline and every 2 years thereafter. Incident cases of new-onset hearing loss were defined as those diagnosed after 1986. Cox proportional hazards multivariate regression was used to adjust for potential confounding factors.

Results

During 369,079 person-years of follow-up, 3488 incident cases of hearing loss were reported. Regular use of each analgesic was independently associated with an increased risk of hearing loss. Multivariate-adjusted hazard ratios of hearing loss in regular users (2+ times/week) compared with men who used the specified analgesic <2 times/week were 1.12 (95% confidence interval [CI], 1.04-1.20) for aspirin, 1.21 (95% CI, 1.11-1.33) for NSAIDs, and 1.22 (95% CI, 1.07-1.39) for acetaminophen. For NSAIDs and acetaminophen, the risk increased with longer duration of regular use. The magnitude of the association was substantially higher in younger men. For men younger than age 50 years, the hazard ratio for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen.

Conclusions

Regular use of aspirin, NSAIDs, or acetaminophen increases the risk of hearing loss in men, and the impact is larger on younger individuals.     

Chronic pain. Clinical management of common causes of geriatric pain

Effective management of chronic pain in older persons is attainable, although unnecessarily elusive. A host of factors can impede assessment and drug management, including impaired cognitive function, multiple potential causes of pain, pharmacokinetics and pharmacodynamics unique to the geriatric population, and clinician anxiety regarding analgesic addiction. In the geriatric population, some of the most prevalent chronic pain management cases involve osteoarthritis, low back pain, and neuropathy. Effective pain management is achieved with analgesics (acetaminophen and nonsteroidal anti-inflammatory drugs), opioids, non-opioid agents (e.g., tricyclic antidepressants, anticonvulsants) and invasive techniques (corticosteroid epidural injections/nerve blocks).     

Frequency of analgesic use and risk of hypertension among men

BACKGROUND: Nonnarcotic analgesics are the most commonly used drugs in the United States. To our knowledge, the association between the use of these analgesics, particularly acetaminophen, and the risk of hypertension among men has not been extensively studied. METHODS: The association between analgesic use and risk of incident hypertension was analyzed in a prospective cohort analysis of 16 031 male health professionals without a history of hypertension at baseline. Detailed information about the frequency of use of acetaminophen, nonsteroidal anti-inflammatory drugs, and aspirin was gathered at baseline and updated 2 years later. The relative risk of incident hypertension during 4 years of follow-up was analyzed using multivariable proportional hazards regression. RESULTS: We identified 1968 incident cases of hypertension. After adjusting for multiple potential confounders, men who used acetaminophen 6 to 7 days per week compared with nonusers had a relative risk for incident hypertension of 1.34 (95% confidence interval, 1.00-1.79; P=.01 for trend). This same comparison resulted in relative risks of 1.38 (95% confidence interval, 1.09-1.75; P=.002 for trend) for nonsteroidal anti-inflammatory drugs and 1.26 (95% confidence interval, 1.14-1.40; P<.001 for trend) for aspirin. We observed similar results when the number of pills per week was analyzed rather than frequency of use in days per week. CONCLUSIONS: The frequency of nonnarcotic analgesic use is independently associated with a moderate increase in the risk of incident hypertension. Given the widespread use of these medications and the high prevalence of hypertension, these results may have important public health implications.