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Jeff Gudin, Abel Gonzalez, Joon Lee
Pain Management and Palliative Care, Englewood Hospital and Medical Center, Englewood, New Jersey, USACorrespondence to: Jeff Gudin, MD. Clinical Instructor, Anesthesiology, Icahn School of Medicine at Mount Sinai, Board Certified Pain Management, Anesthesiology, Palliative Care and Addiction Medicine; Director. Pain Management and Palliative Care, Englewood Hospital and Medical Center, 350 Engle St. Englewood, New Jersey 07631, USA. Email: healthmd@optonline.net; Abel Gonzalez, MD. Department of Internal Medicine, Englewood Hospital and Medical Center, 350 Engle St, Englewood NJ 07631, USA. Email: drabelernesto@yahoo.com; Joon Lee, MD. Pain Management and Palliative Care, Englewood Hospital and Medical Center, 350 Engle St, Englewood NJ 07631, USA. Email: joon.y.lee1982@gmail.com.
Abstract: The treatment of pain in palliative care is often a challenge to clinicians, patients, and their
caregivers. Therapeutic approaches vary and range from drugs to interventional/surgical procedures to
complementary therapies. Although opioids are a mainstay of treatment, many patients succeed on non-
opioid analgesics or improve when non-opioids are added to their regimen. As with any analgesic, the choice
is based upon the type and severity of pain as well as patient specific risk factors involved with that treatment.
Non-opioid analgesics can be used as monotherapy for mild pain and as an adjuvant for moderate to severe
pain. Different from opioids, they have a maximal effect to their dose response; after achieving an analgesic
ceiling, increasing the dose does not offer additional analgesia but increases the risk of adverse effects.
These agents also do not produce physical or psychological dependence and therefore sudden interruption
in treatment does not typically produce drug withdrawal or any abstinence syndrome. This chapter will
describe our current understanding and the utility of non-opioid analgesics, specifically non-steroidal anti-
inflammatory drugs (NSAIDs) and acetaminophen.
Keywords: Non-opioid analgesics; palliative care; non-steroidal anti-inflammatory drugs (NSAIDs)
Received: 09 May 2016; Accepted: 04 August 2016; Published: 16 August 2016.
doi: 10.21037/phe.2016.08.03
View this article at: http://dx.doi.org/10.21037/phe.2016.08.03
analgesics and antipyretics indicated for mild to moderate pain of all types as well as for fever. Different from opioids, The treatment of pain in palliative care is often a challenge they have a maximal effect to their dose response; after to clinicians, patients, and their caregivers. Therapeutic achieving an analgesic ceiling, increasing the dose does approaches vary and range from drugs to interventional/ not offer additional analgesia but increases the risk of surgical procedures to complementary therapies. Although adverse effects. These agents also do not produce physical opioids are a mainstay of treatment, many patients succeed or psychological dependence and therefore sudden on non-opioid analgesics or improve when non-opioids are interruption in treatment does not typically produce drug added to their regimen. As with any analgesic, the choice is withdrawal or any abstinence syndrome.
based upon the type and severity of pain as well as patient Non-opioid analgesics can be used as monotherapy specific risk factors involved with that treatment. This for mild pain and as an adjuvant for moderate to severe chapter will describe our current understanding and the pain. The World Health Organization (WHO) guidelines utility of non-opioid analgesics, specifically non-steroidal recommend non-opioid therapy at all three steps on the anti-inflammatory drugs (NSAIDs) and acetaminophen.
analgesic ladder, either alone or in combination with an Non-opioids such as NSAIDs and acetaminophen are opioid or adjuvant medication or both (1). It is suggested Public Health and Emergency. All rights reserved.
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Neurolytic block therapy Chronic pain without control Spinal stimulators Acute crises of chronic pain Oral administration Transdermal patch Non-malignant pain (with or without adjuvants NSAID, nonsteroidal anti-inflammatory drug; PCA, patient-controlled analgesia.
Figure 1 New adaptation of the analgesic ladder. Reprinted with permission: Vargas-Schaffer G. Is the WHO analgesic ladder still valid?
Can Fam Physician 2010;56:514-7. that unless contraindicated, any analgesic regimen should include non-opioid drugs, even when pain is severe enough to require the addition of an opioid (2). In addition to non- Acetaminophen is one of the most commonly used opioids, adjuvant drugs that provide or enhance analgesia medicines in the United States. It is regularly known may be used at any step to treat concurrent non-nociceptive elsewhere around the world as paracetamol. Although acetaminophen has been shown to have analgesic and The first step on the ladder is the use of non-opioids antipyretic activity, its mechanism of action remains largely for mild to moderate pain; when pain persists or increases, unknown. The effects are thought to be centrally mediated, the ladder suggests a mild opioid such as codeine or but there is some literature that describes a potential hydrocodone be added to (not substituted for) the non- peripheral mechanism of action (4).
opioid. Opioids at step II are often administered in fixed- Acetaminophen is a weak inhibitor of prostaglandin dose combinations with acetaminophen, NSAIDs or aspirin (PG) synthesis in vitro and appears to have very little anti- as these combinations are thought to provide additive and inflammatory activity (5). The chemical name for the perhaps synergistic analgesia. Upward titration of these compound is N-acetyl-para-aminophenol (APAP). When combination products is usually limited by dose-related used according to the label, it has a well-established record toxicity of the non-opioid component. When higher doses of safety and efficacy. It has not been shown to significantly of opioids are necessary, the third step is approached affect platelet function, increase surgical bleeding, or affect whereby separate dosage forms of the opioid and non- kidney function with short term use (6,7). Acetaminophen opioid analgesic should be titrated individually to maximal risks increase with long term use, but it has a high therapeutic efficacy and minimal toxicity. A fourth step of the ladder has index that allows for safe and effective use in treating pain and been proposed to include consideration of interventional fever in a wide range of patients. Although acetaminophen pain management and neurosurgical procedures such as overdose is rare in the context of its broad usage, overdose nerve blocks, neurolysis, spinal cord or brain stimulators can be toxic and is the leading cause of acute liver failure in and other invasive techniques (Figure 1) (3).
the US (8). Acetaminophen may be preferred over NSAIDs Public Health and Emergency. All rights reserved.
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in elderly patients with osteoarthritis because of fewer GI and renal side effects. The American Geriatrics Society Aspirin is a potent inhibitor of both PG synthesis and recommends acetaminophen as the analgesic of choice for platelet aggregation (17). It is a unique NSAID that minor aches and pains in patients older than 50 years (9). In cancer pain, acetaminophen can be added to a mild or strong irreversibly inhibits cyclooxygenase type 1 (COX-1) opioid regimen to increase analgesic effects while decreasing and cyclooxygenase type 2 (COX-2) (18). Platelets have side effects.
markedly limited capacity for protein synthesis allowing Acetaminophen is readily absorbed from the GI tract this inhibition to last the lifetime of the platelet which is allowing administration orally and rectally. Pharmacokinetic about 8 to 12 days. This property of aspirin supports its role studies of rectal administration of acetaminophen showed in decreasing risk of thrombotic events such as myocardial up to 9-fold variation of peak drug concentration, infarction and stroke (19).
often not achieving therapeutic levels (10). The range The recommended dose of aspirin in adults varies by in pharmacokinetic differences could be a result of the indication. The package insert (17) recommends up to inherent variability of venous drainage from the rectum. 3 g per day for osteoarthritis and up to 4 g per day for Drugs administered distally in the rectum bypass the liver, spondyloarthropathies. For acute analgesic and antipyretic whereas drugs administered in the proximal portion drain purposes, most sources recommend 325–650 mg every four into the portal system and are subject to the hepatic first- hours as needed up to 4 g/day (20). Similar to other NSAIDs, pass effect (11).
gastric disturbances and bleeding are common adverse effects An intravenous formulation of acetaminophen was with therapeutic doses of aspirin. Regular aspirin use is approved in the United States in 2010 for the treatment associated with gastrointestinal (GI) bleeding, with risk more of pain and as an antipyretic (12). IV administration is strongly related to dose than duration of use (21).
convenient in the immediate postoperative period, or in Certain individuals display hypersensitivity to aspirin situations where a patient is unable to take medications and present a wide range of clinical manifestations which by mouth (e.g., nothing by mouth status, severe nausea, can lead to severe bronchospasm or anaphylaxis. This odynophagia, or dysphagia), when a faster onset of analgesia may happen within minutes of aspirin ingestion or be a is desired, or when the rectal route is not preferred (13). delayed-type response appearing after days or weeks (22). IV administration may also result in a more rapid onset Aspirin intolerance is a contraindication to therapy with of analgesia with higher peak plasma concentrations and any NSAID because cross-sensitivity can provoke a life- more predictable pharmacokinetics than the oral or rectal threatening, anaphylactic reaction.
formulations (14).
In January 2011, in an effort to promote its safe use, the U.S. Food and Drug Administration (FDA) asked drug manufacturers to limit the strength of acetaminophen NSAIDs are amongst the most widely used agents. in prescription drug products, which are predominantly Compared with placebo, NSAIDs have shown clear combinations of acetaminophen and opioids. The analgesic, antipyretic, and anti-inflammatory effects, recommendation was to limit the amount in these products although their mechanism of action may also lead to to 325 mg per tablet, capsule, or other dosage unit (15).
their toxicities. It is now established that prostanoids (i.e., Despite this change, the prescribing recommendations PGs) play important roles in many cellular responses of 1–2 tablets every 4–6 hours, not exceeding a daily dose and pathophysiologic processes, including modulation of of 4,000 mg was not changed. In addition, Boxed Warnings inflammatory reactions, erosion of cartilage and bone, GI highlighting the potential for severe liver injury and a cytoprotection and ulceration, angiogenesis and cancer, warning highlighting the potential for allergic reactions hemostasis and thrombosis, renal hemodynamics, and (e.g., swelling of the face, mouth, and throat, difficulty progression of kidney disease. NSAIDs, COX-2 inhibitors, breathing, itching, or rash) were being added to the label of and acetylsalicylic acid (aspirin) prevent the formation all prescription drug products that contain acetaminophen. of prostanoids from arachidonic acid. This synthesis of The FDA also requires alcohol warnings for acetaminophen PGs from arachidonic acid is controlled by two separate and anticipates that these actions will help to reduce the risk cyclooxygenase enzymes (COX-1 and COX-2) (23). of severe liver injury and allergic reactions (16).
NSAIDs can be grouped by properties as shown in Table 1, Public Health and Emergency. All rights reserved.
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educed in patients with hepatic failur fect on platelet aggr vailable OTC and as a suspension Hepatotoxicity is the main risk; maximum daily dose alcohol abuse, and possibly in older patients ent: 0.25–0.3 h; Metabolites: 300–600 mg, 3 h; >1 g, 5–6 h; Low doses: 2–3 h; high doses: add 30 h Low doses: 7–8 h; high doses: add 15–30 h maximum daily dose 1,800 mg or 26 mg/kg, whichever is lower Recommended daily then 220 mg q8–12h 600–1,200 mg; qd Drug; brand name, Choline magnesium Motrin, Ortho-McNeil; Non-opioid analgesic agents (continued Public Health and Emergency. All rights reserved.
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es analgesia at the opioid level ed as a simple analgesic and onic painful conditions e RA, ankylosing spondylitis, acute painful o-drug has to be metabolized by the liver for o-drug has to be metabolized by the liver for Higher incidence of adverse ef cannot be consider should not be used in conditions other than moderate shoulder and acute gouty arthritis analgesic efficacy; active metabolite has long half-life analgesic efficacy; active metabolite has long half-life; relatively low risk for GI toxicity Potent NSAID with potential to cause serious adverse events; should be used only for moderately sever acute pain that r for a maximum duration of 5 d; should not be used for active metabolite: 18 h Active metabolite: maximum daily dose <50 or ≥65 kg years old:150 mg in first 24 h, then 120 mg; >50 kg: dose, then 15–30 mg mg loading dose, - Recommended daily 25–50 mg; q8–12h 150–200 mg; bid 50–75 mg; q8–12h <50 or ≥65 kg years dose, then 10–15 mg q6h; >50 kg: 30 then 15–30 mg q6h 200–400 mg; q8h Drug; brand name, Indocin SR, Forte; Suppository; Indocin, Nabumetone; Relafen, Cataflam, Novartis (continued (continued Public Health and Emergency. All rights reserved.
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enal insufficiency , similar risk for r ease risk for serious oved indication in the United egular monitoring ombotic events, myocar fect on platelet function. As with other ed with nonselective COX-1 and COX-2 , congestive heart failur escription NSAIDs, may incr , pain is an FDA-appr High incidence of peptic ulcer with use of 40 mg for COX-2 selective at low doses Should not be used for >1 wk inhibitors: less risk for GI toxicity olonged use and/or high doses, r -the-counter; CHF e, and patients taking multiple drugs, the starting dose and maximum daily eased bleeding risk, concomitant use of an anticoagulant (e.g., warfarin), r ease with duration of use. eatine), and liver function tests ar maximum daily dose oidal anti-inflammatory drug; OTC, over oke. This risk may incr Recommended daily 200–400 mg; q6–8h , contraindictions to NSAID administration: incr enal function tests (blood ur Drug; brand name, Mobic, Boehringer om Pain Medicine News 2008;7:1-8]. NSAID, non-ster (continued , the starting dose should always be individualized. In older patients, patients with ra dose should be lower rec renal thr bleeding (stool guaiac), r States. permission fr Public Health and Emergency. All rights reserved.
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but are generally classified by the way they interact with inhibited or induced by other drugs or compete with other cyclooxygenase: non-selective (ns) COX-1 and COX-2 drugs (known as substrates) for metabolism, resulting in versus selective COX-2 inhibitors.
clinically significant drug-drug interactions that can cause unanticipated therapeutic failures or adverse reactions. Polymorphisms in CYP2C9 (i.e., poor metabolizers) or NSAIDs: physiology/mechanism of action
the addition of other CYP450 enzyme inhibitors may As mentioned in the chapter on pain pathophysiology, cause adverse effects related to elevated drug serum levels. analgesics are thought to reduce the release of excitatory Knowledge of the most important drugs metabolized by nociceptive chemicals and slow the transmission of pain cytochrome P450 enzymes (substrates), as well as the most signals from the periphery to the central nervous system. potent inhibiting and inducing drugs, can help minimize the When damage to the cell membrane occurs, an inflammatory possibility of adverse drug reactions and interactions. This response is triggered, breaking down arachidonic acid becomes more important as we consider the widespread use by enzymes called cyclooxygenase (COX), including its of NSAIDs along with an increase in polypharmacy in our isoforms COX-1 and COX-2. This cascade produces PG aging population. and its breakdown products prostacyclin and thromboxane. Whereas COX-1 enzymes are constitutive- always actively NSAIDs: therapeutic benefits
producing PGs that regulate renal, GI, and platelet function, COX-2 enzymes are inducible-activated following a trauma The role of NSAIDs in cancer and other conditions has or an inflammatory stimulus (27). Once PGs are produced in been well established for the treatment of mild-moderate response to a noxious stimulus, they sensitize the peripheral pain, for bone pain and in association with opioids in the nerve endings that form primary pain receptors found in treatment of moderate-to-severe pain. The use of NSAIDs skin, connective tissues, and visceral organs. The cascade has been shown to be opioid sparing in cancer and other that ensues can then trigger a prolonged increase in the pain syndromes, i.e., post-operative pain-reducing the excitability of neurons in the periphery, as well as in central overall need for opioids or allowing for the use of lower nociceptive pathways-phenomenon known as peripheral and central sensitization (28). Though traditionally viewed as They lack the undesired opioid effects such as respiratory peripherally acting agents, it is well recognized that NSAIDs depression, somnolence, constipation, and the potential also exert their analgesic effects through inhibition of COX of developing physical dependence or addiction. Based on in the spinal cord and brain (CNS) (29). the evidence that osteolytic activity in bone metastases is NSAIDs are completely absorbed in the GI tract, with mediated at least in part by PGs, NSAIDs are the first line food only minimally affecting plasma levels, although an of therapy in malignant bone pain and should be used in increase in gastric pH has been shown to reduce NSAIDs any cancer pain if no contraindication exists (2). absorption (30). From a pharmacokinetic standpoint, Interestingly, a 2010 drug class review noted high- NSAIDs do not undergo first-pass elimination. They are strength evidence that there were no significant efficacy highly bound to plasma proteins resulting in a low volume differences between individual oral NSAIDs (34). distribution, and this high affinity for plasma proteins disposes them to displace other drugs from binding sites, including warfarin and other NSAIDs (31).
Most NSAIDs are broken down by the cytochrome The entire class of NSAIDs is now under increased scrutiny P450 2C9 (CYP2C9) hepatic enzyme system to inactive as unwanted side effects may not be class-specific. The metabolites that typically are excreted in the urine, though most significant NSAID adverse events (AEs) are associated some drugs are also excreted in bile (32). Interactions with with platelet inhibition, GI, renal and cardiovascular (CV) warfarin, beta blockers, antidepressants, antiepileptic drugs, toxicity. These have been attributed to NSAID induced and statins often involve the cytochrome P450 enzymes. blockade of PGs. The selective COX-2 inhibitors were Genetic variability (polymorphisms) in the cytochrome developed under the assumption that the constitutive COX- P450 enzymes may influence a patient's response to many 1 enzyme would be spared causing fewer side effects than commonly prescribed drug classes, including NSAIDs. traditional NSAIDs (35). However, recent studies have As a review, the metabolism of these agents can be indicated that COX-2 is also constitutively expressed and Public Health and Emergency. All rights reserved.
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that its inhibition may exacerbate inflammation, impair NSAID induced nephropathy include edema (sodium and ulcer healing, and decrease the formation of prostacyclin. fluid retention) and hypertension. The black box warning Therefore, all NSAIDs have increased risk for thrombosis, indicates that the use of NSAIDs can promote sodium myocardial infarction, renal impairment, hypertension, retention in a dose-dependent manner, through a renal stroke, and liver toxicity (36). mechanism, which can result in increased blood pressure In the GI tract, PGs exert a protective effect by reducing and/or exacerbation of CHF (34). Regular monitoring of acid secretion, promoting gastric mucosal blood flow, blood pressure is necessary in all patients, especially the and stimulating bicarbonate and mucus production (37). elderly, who are on antihypertensive therapy (42).
By inhibiting COX-1, NSAIDs suppress these protective In addition to risk of increased blood pressure and PGs and also cause local irritation by direct contact with exacerbation of CHF, use of some NSAIDs is associated the GI lining. GI toxicity varies from mild (dyspepsia, with an increased incidence of CV AEs such as myocardial nausea, abdominal pain, and reflux) to severe symptoms infarction, stroke or thrombotic events which can be fatal. (ulcer, bleeding, and perforation). These events can occur The risk increases with dose and duration of use. Patients at any time during use and without warning. Elderly with risk factors or preexisting CV disease may be at patients are at greater risk for serious GI events and greater risk (3). A 2011 meta-analysis suggested that among clinicians are advised to consider both the safety as well as a number of NSAIDs analyzed, naproxen seemed least effectiveness of NSAIDs in this population (34). The risk harmful for CV safety (43). of GI AEs is further increased in those with Helicobacter Although the exact mechanism of this NSAID induced pylori infection, heavy alcohol consumption, or other cardiac toxicity is not fully understood, it seems to be linked risk factors for mucosal injury, including concurrent use to the relative imbalance in prostacyclin and thromboxane of glucocorticoids (38). Co-administration of the PGE1 production, resulting in a prothrombotic state (44). analog, misoprostol, or proton pump inhibitors (PPIs) Therefore, caution should be exercised in prescribing in conjunction with NSAIDs can be beneficial in the NSAIDs to any patient with ischemic heart disease, CHF prevention of these symptoms (39), although their benefits [congestive heart failure (NYHA II-IV)], or cerebrovascular may be limited to areas exposed to gastric acid (i.e., the disease. NSAIDs are contraindicated for treatment of proximal GI structures).
perioperative pain in the setting of coronary artery bypass Symptomatic ulcers and ulcer complications develop in graft (CABG) surgery.
only 2% to 4% of patients taking NSAIDs for a year (40). Clinicians have come to recognize that toxicity can occur Even low-dose aspirin, with or without enteric coating, is at any time or with any duration of use with NSAIDs and associated with an increased risk of UGI bleeding. Although from an overall risk standpoint, regardless of the NSAID the risk appears small, the millions of U.S. patients taking chosen, the lower the dose utilized- the lower the risk to the NSAIDS for arthritis or aspirin for CV prophylaxis translate into a large number of patients at risk.
In 2005, the FDA requested that manufacturers of Nephrotoxicity has also been observed for all NSAIDs. all NSAIDs produce a patient medication guide for In patients with congestive heart failure (CHF), hepatic these products and make changes to their product label cirrhosis, chronic kidney disease, hypovolemia, and other (package insert) for both prescription and over-the-counter states of activation of the renin-angiotensin system, the (OTC) NSAIDs. They mandated inclusion of a boxed PG effect on renal function becomes more significant. PGs warning highlighting the potential for increased risk of are necessary for the renal excretion of several electrolytes, cardiovascular (CV) events and the well described, serious, toxins, and drug metabolites. By inhibiting the synthesis potential life-threatening GI bleeding associated with their of PGs, NSAIDs decrease the renal clearance of these materials. PGs normally cause vasodilation of the afferent In 2013, the FDA approved an NSAID developed using arterioles of the glomeruli. This helps maintain normal a proprietary (SoluMatrix Fine Particle™) technology glomerular perfusion and glomerular filtration rate (GFR), which altered the absorption properties of diclofenac, an indicator of renal function. The renal risks increase with suggesting the prospect of pain relief at lower doses— chronic or high dose NSAIDs, urinary tract infections, at least 20% lower than currently available diclofenac and the use of certain diuretics and angiotensin converting products. Further clinical trials are warranted for this enzyme (ACE) inhibitors (41). Common AEs noted with and other emerging NSAID technologies to determine Public Health and Emergency. All rights reserved.
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their long term safety and efficacy. This technology pain. Although clinicians need to recognize the risks was developed to address FDA's public health advisory associated with these therapeutic agents, unless there is recommending that NSAIDs be used at the lowest a contraindication, all analgesic regimens should include effective dose for the shortest duration of time consistent non-opioid drugs, even when the pain is severe enough to with individual patient treatment goals (46).
require the addition of an opioid. With the increased GI and CV risks associated with oral NSAIDs, topical NSAIDs are gaining in popularity with controversial evidence supporting their use. A recent review supported their use in knee and hand osteoarthritis, with no evidence of benefit for other chronic painful Conflicts of Interest: This article has been originally published conditions (47). A 2010 review of NSAIDs noted that both in the book The Art and Science of Palliative Medicine.
diclofenac 1.5% topical solution and 1.0% topical gel had significantly greater mean changes in pain subscale scores than placebo (34). Of the topical NSAIDs approved in the United States, both diclofenac gel and diclofenac solution Ventafridda V, Saita L, Ripamonti C, et al. WHO guidelines have demonstrated efficacy in the management of OA for the use of analgesics in cancer pain. Int J Tissue React of the knee. Current evidence shows that combining a topical NSAID with an oral NSAID confers no additional 2. Acute Pain Management Guideline Panel. Acute pain therapeutic benefit over either agent used alone, but it does management: operative or medical procedures and trauma: increase the number of AEs (48). clinical practice guidelines. Rockville (MD): Agency for Healthcare Policy and Research, Public Health Service, US Department of Health and Human Services 1992. Ketorolac tromethamine is an IV NSAID formulation that acute.htm, accessed December 16, 2013.
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doi: 10.21037/phe.2016.08.03
Cite this article as: Gudin J, Gonzalez A, Lee J. Nonopioid
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r 2010 British HIV Association HIV Medicine (2010) SHORT COMMUNICATION Introduction of pharmacogenetic screening for thehuman leucocyte antigen (HLA) B*5701 variant inPolish HIV-infected patients M Parczewski, M Leszczyszyn-Pynka, A Wnuk, A Urban˜ska, K Fuksin˜ska, D Bander and A Boron˜-Kaczmarska Department of Infectious Diseases and Hepatology, Pomeranian Medical University, Szczecin, Poland

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UNITED STATES DISTRICT COURT NORTHERN DISTRICT OF ILLINOIS EASTERN DIVISION WENDY DOLIN, Individually and as Independent Executor of the ESTATE OF STEWART DOLIN, deceased, Judge James B. Zagel v. SMITHKINE BEECHAM CORPORATION d/b/a GLAXOSMITHKINE, a Pennsylvania Corporation; and MYLAN INC., a Pennsylvania Corporation, Defendants.