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T h e in it iat in g event is a t ran sient bact eremia purchase generic quibron-t online, wh ich may be a r esu lt of mucosal injury buy discount quibron-t online, as in dental extraction quibron-t 400 mg for sale, or a complication of the use of intravascular cat h et er s buy quibron-t 400 mg without a prescription. P r eviou sly damaged, abnormal, or prost het ic valves form veget at ions, wh ich are composed of plat elet s and fibrin, and are relat ively avascular sites where bacteria may grow protected from im mu n e at t ack. Serial blood cultures are the most important step in the diagnosis of endocarditis. Acutely ill patients should have three blood cultures obtained over a 2- to 3-hour period prior to initiating antibiotics. In subacute disease, three blood cultures over a 2 4 -hour period maximize t he diagnost ic yield. O f course, if pat ient s are crit ically ill or hemodynamically unst able, no delay in init iat ing t h erapy is appropriate, and cu lt ures are obt ain ed on present at ion, even wh ile broad-spect r um ant ibiot ics are administered. Usually it is not difficult to isolat e t he infect ing organism, because the hallmark of infective endocarditis is sustained bacteremia; thus, all blood cul- tures often are positive for the microorganism. Table 12– 1 lists typical organisms, fr equ en cy of in fect ion, an d associat ed con d it ion s. The clinical features, blood cultures, and echocardiography are used to diagnose cases of infective endocarditis using the highly sensitive and specific Duke criteria. Endocarditis is considered to definitely be present if the patient satisfies two major criteria; one major and three minor criteria; or five minor criteria (Table 12– 2). O t h er car diac complicat ion s are int racar diac abscesses an d con du ct ion dist ur ban ces caused by septal involvement by infection. Systemic arterial embolization may lead to splenic or renal infarct ion or abscesses. Veget at ions may embolize t o t he coronary circulat ion, cau sin g a myocardial in far ct ion, or t o the br ain, cau sing a cerebr al infarct ion. A stroke syndrome in a febrile patient should always suggest the pos- sibilit y of endocarditis. In fect ion of the vasa vasor um may weaken the wall of major arteries and produce mycotic aneurysms, which can occur anywhere but are most common in the cerebral circulation, sinuses of Valsalva, or abdominal aort a. T hese aneurysms may leak or rupture, producing sudden fat al int racranial or ot her hemorrhage. Ant ibiot ic t reat ment is usually begun in the hospit al but because of the pro- longed nat ure of t h erapy is oft en complet ed on an out pat ient basis wh en the patient is clinically stable. If the or gan ism is susceptible, such as most St r eptococcus species, penicillin G is the agent of choice. For Staphylococcus aureus, nafcillin is t he drug of choice, oft en used in combinat ion with gentamicin init ially for synergy, t o help resolve bact eremia. T herapy for int ra- ven o u s d r u g u ser s sh o u ld b e d ir ect ed again st S aureus. Vancomycin is used when methicillin-resistant S aur eus or coagulase-negative staphylococci are present. Deciding appropri- ate therapy for culture-negative endocarditis may be challenging and depends on the clinical situation. Table 12– 3 summarizes the commonly recognized indicat ions for surgical int er- ven t io n : valve excision and replacement. Patients at high risk for developing infective endocarditis benefit from antibiotic prophylaxis prior to dent al procedures. Alternatives for use in these situa- tions include ampicillin, cephalosporins, and clindamycin. Good dental hygiene and proper denture fitting to prevent reinfection of damaged heart valves from oral flora. R ep eat ech o car d io gr ap h y in 6 week s t o en su r e the veget at io n s h ave resolved. H e has three blood cultures positive with Candida spp and suddenly develops a cold blu e t oe. Repeat echocardiography to see if the large aortic vegetation previously seen has now embolized. C ar d iovascu lar su r ger y co n su lt at io n fo r ao r t ic valve r ep lacem en t. H eart valves damaged by endocarditis are more susceptible to infection, so good dental hygiene is import ant, but in this case, t he organism came from t he int est inal t ract, not the mouth, and the possibility of malignancy is most important to address. Serial echocardiography would not add to the patient’s care after success- fu l t h er apy becau se veget at ion s become or gan ized an d p er sist for m on t h s or year s wit h ou t lat e em b oliz at ion. P r op h ylact ic valve r ep lacem en t would n o t be indicated because the prosthetic valve is even more susceptible to reinfec- tion than the damaged native valve and would actually increase the risk of cer ebr al in far ct ion or ot h er syst em ic emboli as a con sequ en ce of t h r ombu s format ion, even if adequat ely ant icoagulat ed. Fungal endocarditis, which occurs in intravenous drug users or immu- nosuppressed persons with indwelling catheters, frequently gives rise to large friable veget at ions wit h a h igh risk of embolizat ion (oft en t o the lower ext remit ies) and is very difficult t o cure wit h ant ifungal medicat ions. Repeat echocardiography would not add to the patient’s care because the clinical diagnosis of peripheral embolization is almost cert ain, and it would not change t he management. Medical t herapy wit h any ant ifungal agent is unlikely to cure t his infect ion. Mycot ic aneu- rysms may occur in any artery as a consequence of endocarditis and can cause lat e embolic complicat ions, but in this case, the source probably is the h eart. Prior endocarditis damages valvular surfaces, and these patients are at increased risk for reinfect ion during a t ransient bact eremia, as may occur dur- ing dent al procedures or some ot her G I or genit ourinary t ract procedures. All of the other conditions mentioned have a negligible risk of endocarditis, the same as in the general populat ion, and ant ibiot ic prophylaxis is not recom- mended by the American H eart Association. Th e la rg e m a jo rit y o f rig h t -sid e d endocarditis is caused by S a u r e u s. In fect ive en d ocar d it is: diagnosis, antimicrobial therapy, and management of complications. Blood culture negative endocarditis in a reference center: etiologic diagnosis of 348 cases. He has a history of chronic stable angina, hypercholesterolemia, and hypertension, for which he takes aspirin, atenolol, and simvastatin. He has experienced pain in both calves and feet with walking for several years, and the pain has gradually progressed so that he can now walk only 100 ft before he has to stop because of pain. He occa- sionally has experienced mild pain in his feet at night, but the pain usually gets better when he sits up and hangs his feet off the bed. This time, the pain was more severe and did not improve, and he now feels like the foot is numb and he cannot move his toes. On p h ysica l e xa m in at io n, h e is a fe b rile, wit h h e a rt ra t e 72 b p m a n d b lo o d p re s- sure 125/74 mm Hg. His chest is clear to auscultation; his heart rhythm is regular with a nondis- placed apical impulse, an S g a llo p, a n d n o m u rm u rs. He has bilateral femoral bruits, and palpable femoral and popliteal pulses bilaterally. His pedal pulses are diminished; they are present on the right but absent on the left. The left distal leg and foot are pale and cold to touch, with very slow capillary refill. H e previously had symptoms of bilateral calf claudication, but now has the sudden onset of pain, pallor, and pulselessness in the left foot. Most likely diagnosis: Acute limb ischemia, either thrombotic arterial occlusion or embolism from a more proximal source. Understand the clinical presentation of a patient with atherosclerotic periph- eral vascular disease, including acut e limb ischemia. Co n s i d e r a t i o n s This patient has diffuse atherosclerotic vascular disease, including coronary artery disease, carotid disease, and peripheral vascular disease. H is history of calf pain with walking, but resolution with rest, is classic for claudication. Recent ly, the per fu sion of his left leg likely was worsening, requiring his waking up and dangling his leg to enable blood flow and t o help t he pain. T h e pat ient complain s of the su dden on set of pain, pallor, and pulselessness, in d icat ive of acut e ar t er ial occlu sion. H is limb isch em ia may result from acute arterial occlusion caused by an embolus, usually arising from a dislodged t hrombus from t he heart, or from t he aort a or a large proximal art ery such as the iliac. D epending on the level of occlusion, the pat ient may require urgent arterial thromboembolectomy. H yper t en sion, dyslip - idemia, and elevat ed homocyst eine levels also play significant roles.
Bact eremia as a consequence of S aur eus cheap quibron-t 400mg free shipping, gram-negative organisms purchase 400mg quibron-t overnight delivery, and fungemia caused by Candida spp respond poorly to antimicrobial therapy alone purchase genuine quibron-t line, so prompt removal of the catheter is recommended 400 mg quibron-t amex. Pre ve n t io n Becau se of the ser iou s complicat ion s associat ed wit h n eut r op en ia, pr event ive mea- sures are crit ical in cancer pat ient s who are receiving ch emot herapy. T h ey should be immunized against pneumococcus and influenza, but administration of live virus vaccin es, su ch as m easles- m u m p s- r u b ella o r var icella z o st er, is co n t r ain d icat ed. It is somet imes used once a neutropenic patient develops a fever, but its use at that point is contro- ver sial. P r o p h ylact ic u s e o f o r al q u in o lo n es t o p r even t gr am - n egat ive in fect io n o r ant ifungal agent s to prevent Candida infection may reduce certain types of infec- tion but may select for resistant organisms and is not routinely used. Because slight trauma to mucosal surfaces can cause bacteremia, careful oral hygiene, avoidance of rectal thermometers or rectal examinations, and skin care are also important. He was hospitalized 7 days ago for fever to 102°F with an absolute 3 neutrophil count of 100 cells/ mm, an d h e h as been placed on int r aven ou s imipenem and vancomycin. Last cycle, she developed neut ropenia with an 3 absolut e neut rophil count of 350 cells/ mm, wh ich h as n ow resolved. Coagulase-negative staphylococci, such as S epider midis, along wit h S aureus, are the most common et iology of cat h et er-r elat ed in fect ion s. Antifungal therapy should be added when the fever is persistent despite broad-spectrum antibacterial agents. Patients with neutropenia, defined as an absolute neut rophil count less than 1000 cells per uL, are a greater risk for bacterial (gram positive and gram negative) and fungal infections such as cau sed by C an d ida albican s an d Asp er gillu s. Granulocyte colony-stimulating factor given after chemotherapy can decrease the duration and severity of neutropenia and the subsequent risk of sepsis. For S a ur eus, g ra m -n e g a t ive ro d s, o r fu n g a l catheter infections, the catheter usually requires removal. Wh e n yo u w a lk in t o the r o o m, h e is ly in g o n the e xa m in a t io n t a b le, o n h is s id e, with his arm covering his eyes. When you gently ask how he has been feeling, he says that for the past 3 days he has had fever, body aches, and a progressively worsening headache. He h as h ad so m e rh in o rrh e a, b u t n o d iarrh e a, co u g h, o r n asa l co n g e s- tion. On examination, he has no skin rash, but his pupils are difficult to assess because of photophobia. Neurologic examina- tion reveals no focal neurologic deficits, but passive flexion of his neck worsens his headache, and he is unable to touch his chin to his chest. H e has no respiratory or gastrointestinal symp- toms, but now has developed photophobia. H is physical examinat ion is generally unremarkable with a non- focal n eurologic examinat ion but some n eck st iffn ess, suggest ing men in geal irrit a- tion. Co n s i d e r a t i o n s This 20-year-old college student has headache, nausea, photophobia, fever, and neck pain and st iffness— all suggest ive of meningit is, which could be bact erial or vir al. If he had a purpuric skin rash, one would be suspicious of Neisseria meningitidis, an d appr opr iat e ant i- biotics should be administered immediately. Dosing of antibiotics in suspected meningococcal infection should not await the performance of any diagnostic test because progression of the disease is rapid, and mortality and morbidity are ext remely h igh even when ant ibiot ics are given in a t imely manner. W hen focal brain parenchymal infect ion is caused by bacteria, it is usually termed cer ebr i t i s or abscess. The incidence is dropping due to the use of the pneumococcal and hemophilus influenza vaccines. H owever, the disease is st ill dangerous, wit h case fat alit y rat e wit h t reat ment of approximat ely 10% t o 20%, and serious morbidit y such as seizures, hearing loss, or brain damage. Bact er ial m en in git is is the m o st com m on p u s-for m in g in t r acr an ial in fect ion, with an incidence of 2. The microbiology of the disease has ch an ged somewh at sin ce the int r odu ct ion of the Haemophilus influenzae type B vaccin e in the 1 9 8 0 s. N ow Streptococcus pneumoniae is the most common bacterial isolate, wit h N meningitidis a close second. Group B St r eptococcus or St r ept ococcu s agalactiae occurs in approximately 10% of cases, more frequently in neonates or in patients older than 50 years or with chronic illnesses such as diabetes or liver dis- ease. Resistance to penicillin and some cephalosporins is now of great concern in t he t reat ment of S pneumoniae. Bact er ia u su ally seed the m en in ges h em at o gen ou sly aft er colon iz in g an d in vad - ing t he nasal or oropharyngeal mucosa. O ccasionally, bact eria direct ly invade t he int racranial space from a sit e of abscess format ion in the middle ear or sinuses. The gr avit y an d r apidit y of pr ogr ession of d isease d epen d on bot h h ost d efen se an d organism virulence characteristics. For example, patients with defects in the com- plement cascade are more susceptible to invasive meningococcal disease. Staphylococcus aur eus and Staphylococcus epider midis are com m on cau ses of m en in git is in pat ient s following neurologic procedures such as placement of vent riculo perit oneal shunts. Pat ient s may also complain of ph ot oph obia, nau sea an d vo m it in g, an d m o r e n o n sp ecific co n st it u t io n al sym p t o m s. Ap p r o xim at ely 7 5 % o f patients will experience some confusion or altered level of consciousness. Some physical examination findings may be useful in the evaluation of a patient wit h suspected meningit is. Nuchal rigidity is demonstrated when passive or active flexion of the n eck r esu lt s in an in abilit y t o t ou ch the ch in t o the ch est. The knee is then passively extended, and t he test is posit ive if this maneuver elicit s pain. Brudzinski sign is p osit ive if the supine patient flexes the knees and hips when the neck is passively flexed. N either sign is very sensit ive for t he presence of meningeal irrit at ion, but, if present, bot h are highly specific. Papilledema, if present, would in dicat e increased intracranial pressure, an d focal n eur ologic sign s or alt ered level of con sciou sn ess or seizur es may reflect ischemia of the cerebral vasculature or focal suppuration. Di e re n t ia l Dia g n o sis The differential diagnosis of bacterial meningitis is fairly limited and can be nar- rowed depending on the patient’s age, as discussed earlier, exposure history, and cou r se of illn ess. T h ese in clu d e enteroviruses, wh ich t en d t o be more common in the summer an d fall, wh en pat ient s may present with severe headache, accompanied by symptoms of gastroenteritis. Rick- ettsial disease, specifically Rocky Mount ain spotted fever, may also present with meningitis. Intracranial empyema, or brain or epidural abscess, should be consid- ered, especially if the pat ient has focal neurologic findings. The one nonsuppurat ive diagnosis in the differential is subarachnoid hemorrhage. T h ese pat ient s present wit h sudden onset of t he “worst headache of t heir lives” in t he absence of ot her sympt oms of infect ion. Blood cult ures sh ould be obt ained in all pat ient s wit h suspect ed meningit is. If enough fluid is available, it should also be sent for cell count and glucose and protein levels. Latex agglutination tests for S pneumoniae and H influenzae can be useful in patients pretreated with antibiotics, and, although not very sensitive, they are highly specific. The most critical issue in a patient with suspected bacterial meningitis, however, is the initiation of antibiotics. During the course of treatment, most patients will undergo some cerebral imag- ing studies. Within 2 to 15 daysof thestart of theillness,periodicsharp and slow wave complexes originat ing wit hin t he temporal lobes can be demonst rated at 2- to 3-second intervals. W hen the purpuric skin lesions are present, skin biopsy may demonstrate N meningitidis and can be helpful in the diagnosis. Th e r a p y Treatment of meningitis often is empiric until specific culture data are available. Becau se of the gr owin g in cid en ce of r esist an t pn eu mococci as well as men in go- cocci, the r ecom m en d ed empir ic t h er apy in m ost ar eas is a high-dose third-genera- tion cephalosporin given concurrently with vancomycin. Gram-negative enteric Am p ic illin + c e fo t a xim e Va g in a l o r g a n is m s bacteria (Es c h e r i c h i a c o l i ) common and group Bstreptococcus 2. S p n e u m o n ia e Ce fo t a xim e (o r c e ft r ia x- Pre vio u s t o vaccin e, 2.
In contrast buy discount quibron-t 400mg on-line, it would be inappropriate to combine two thiazide diuretics or two beta blockers or two vasodilators buy quibron-t 400mg lowest price. Second order 400 mg quibron-t with visa, when drugs are used in combination cheap quibron-t 400 mg without a prescription, each can be administered in a lower dosage than would be possible if it were used alone. Third, when proper combinations are selected, one agent can offset the adverse effects of another. However, if a vasodilator is combined with a beta blocker, reflex tachycardia will be minimal. Dosing For each drug in the regimen, dosage should be low initially and then gradually increased. As a result, sympathetic reflexes offer less resistance to the hypotensive effects of therapy. Individualizing Therapy Patients With Comorbid Conditions Comorbid conditions complicate treatment. Two conditions that are especially problematic—renal disease and diabetes—are discussed here. Preferred drugs for patients with these and other comorbid conditions are shown in Table 39. Drugs to avoid in patients with specific comorbid conditions are summarized in Table 39. Verapamil Diltiazem Coronary artery Hydralazine Reflex tachycardia induced by hydralazine can precipitate an anginal disease attack. Post–myocardial Hydralazine Reflex tachycardia induced by hydralazine can increase cardiac infarction work and oxygen demand. Diuretics Renal K -sparing diuretics+ Use of these agents can lead to dangerous accumulations of insufficiency K supplements+ potassium. Diabetes Thiazides Thiazides and furosemide promote hyperglycemia, and beta blockers mellitus Furosemide suppress glycogenolysis and can mask signs of hypoglycemia. Furosemide Hyperkalemia K -sparing diuretics+ These drugs cause potassium accumulation. Furosemide Collagen Hydralazine Hydralazine can precipitate a lupus erythematosus–like syndrome. Nephrosclerosis secondary to hypertension is among the most common causes of progressive renal disease. Pathophysiologic changes include degeneration of renal tubules and fibrotic thickening of the glomeruli, both of which contribute to renal insufficiency. Hence, in the absence of contraindications, all patients should get one of these drugs. In patients with advanced renal insufficiency, thiazide diuretics are ineffective, hence a loop diuretic should be employed. In diabetic patients, as in nondiabetic patients, beta blockers and diuretics can decrease morbidity and mortality. Keep in mind, however, that beta blockers can suppress glycogenolysis and mask early signs of hypoglycemia and therefore must be used with caution. Thiazides and loop diuretics promote hyperglycemia and hence should be used with care. Hypertension develops earlier, has a much higher incidence, and is likely to be more severe. As a result, black people face a greater risk for heart disease, end-stage renal disease, and stroke. Compared with the general population, blacks experience a 50% higher rate of death from heart disease, are twice as likely to die of stroke, and are 6 times more likely to experience hypertension-related end-stage renal disease. We know that blacks and whites respond equally to treatment (although not always to the same drugs). The primary problem is that, among black people, hypertension often goes untreated until after significant organ damage has developed. If hypertension were diagnosed and treated earlier, the prognosis would be greatly improved. Because blacks have a high incidence of salt sensitivity and cigarette use, lifestyle modifications are an important component of treatment. Controlled trials have shown that diuretics can decrease morbidity and mortality in blacks. The incidence of secondary hypertension in children is much higher than in adults. Accordingly, efforts to diagnose and treat an underlying cause should be especially diligent. For children with primary hypertension, treatment is the same as for adults—although doses are lower and should be adjusted with care. Although the newer guidelines may be more lax, they do not serve as a substitute for clinical judgment. Pregnant women Drugs of choice in treating pregnant women with mild preeclampsia include labetalol and methyldopa. Magnesium sulfate is used in the prevention of seizures in severe preeclampsia or for treatment of seizures in eclampsia. Beta blockers, such as women metoprolol, appear safe for the breastfeeding infant. Caution must be taken to avoid overdiuresis when using diuretics in the older-adult population. Because cardiovascular reflexes are blunted in older adults, treatment carries a significant risk of orthostatic hypotension. Accordingly, initial doses should be low—about one-half those used for younger adults—and dosage escalation should be done slowly. Minimizing Adverse Effects Antihypertensive drugs can produce many unwanted effects, including hypotension, sedation, and sexual dysfunction. Simply put, if one drug causes effects that are objectionable, a more acceptable drug should be substituted. The best way to identify unacceptable responses is to encourage patients to report them. Adverse effects caused by exacerbation of comorbid diseases are both predictable and avoidable. Other conditions that can be aggravated by antihypertensive drugs are listed in Table 39. To help avoid drug-disease mismatches, the medical history should identify all comorbid conditions. With this information, the prescriber can choose drugs that are least likely to make the comorbid condition worse. High initial doses and rapid dosage escalation can increase the incidence and severity of adverse effects. Promoting Adherence The major cause of treatment failure in patients with chronic hypertension is lack of adherence to the prescribed regimen. In this section we consider the causes of nonadherence and discuss some solutions. Why Adherence Is Often Hard to Achieve Much of the difficulty in promoting adherence stems from the nature of hypertension itself. Hypertension is a chronic, slowly progressing disease that, through much of its course, is devoid of overt symptoms. Because symptoms are absent, it can be difficult to convince patients that they are ill and need treatment. In addition, because there are no symptoms to relieve, drugs cannot produce an obvious therapeutic response. In the absence of such a response, it can be difficult for patients to believe that their medication is doing anything useful. Because hypertension progresses very slowly, the disease tends to encourage procrastination. For most people, the adverse effects of hypertension will not become manifest for many years. Realizing this, patients may reason (incorrectly) that they can postpone therapy without significantly increasing risk. Lastly, antihypertensive drugs can cause a number of adverse effects, ranging from sedation to hypotension to impaired sexual function. It is difficult to convince people who are feeling good to take drugs that may make them feel worse. Some people may decide that exposing themselves to the negative effects of therapy today is paying too high a price to avoid the adverse consequences of hypertension at some indefinite time in the future.
The best way to ensure an accurate report is to ask the right questions and listen carefully to the answers buy discount quibron-t online. The following information should be obtained: Onset and temporal pattern: When did your pain begin? Ask patients to point to the exact location of the pain buy quibron-t american express, either on themselves buy quibron-t online now, on you discount 400 mg quibron-t with mastercard, or on a full-body drawing. Intensity: On a scale of 0 to 10, with 0 being no pain and 10 the most intense pain you can imagine, how would you rank your pain now? Impact: How does the pain affect your ability to function, both physically and socially? For example, does the pain interfere with your general mobility, work, eating, sleeping, socializing, or sex life? Physical and Neurologic Examinations The physical and neurologic examinations help to further characterize the pain, identify its source, and identify any complications related to the underlying pathology. The clinician should examine the site of pain and determine whether palpation or manipulation makes it worse. For example, if the patient has hip pain, the assessment should determine whether the pain actually originates in the hip or if it is referred pain caused by pathology in the lumbar spine. For example, patients with back pain should be evaluated for impaired motor and sensory function in the limbs and for impaired rectal and urinary sphincter function, which may indicate spinal cord involvement. Diagnostic Tests Diagnostic tests are performed to identify the underlying cause of pain (e. Psychosocial Assessment Psychosocial assessment is directed at both the patient and his or her family. The objective is to determine the efficacy of treatment and to allow early diagnosis and treatment of new pain. Each time an analgesic drug is administered, pain should be evaluated after sufficient time has elapsed for the drug to take effect. Because most patients are treated at home, patients and caregivers should be taught to conduct and document pain evaluations. The prescriber will use the documented record to make adjustments to the pain management plan. Drug Therapy Analgesic drugs are the most powerful weapons we have for overcoming cancer pain. Because analgesics are so effective, drug therapy is the principal modality for pain treatment. With the nonopioid and adjuvant analgesics, there is a ceiling to how much relief we can achieve. The second step—for more severe pain—adds opioid analgesics of moderate strength (e. Adjuvant analgesics, which are especially effective against neuropathic pain, can be used on any step of the ladder. Accordingly, if a patient has intense pain at the outset, then treatment can be initiated with an opioid (step 2), rather than trying a nonopioid first (step 1). Specifically, if the patient reports pain in the 4 to 10 range, then treatment should start directly with an opioid; an initial trial with a nonopioid is considered unnecessary. If the patient reports pain in the 1 to 3 range, then treatment usually begins with a nonopioid, although starting with an opioid remains an alternative. It is common practice to combine an opioid with a nonopioid because the combination can be more effective than either drug alone. When pain is only moderate, opioids and nonopioids can be given in a fixed-dose combination formulation, thereby simplifying dosing. However, when pain is severe, these drugs must be given separately because, with a fixed-dose combination, side effects of the nonopioid would become intolerable as the dosage grew large and hence would limit how much opioid could be given. Drug therapy of cancer pain should adhere to the following principles: • Perform a comprehensive pretreatment assessment to identify pain intensity and the underlying cause. There is a ceiling to how much pain relief nonopioid drugs can provide, so there is no benefit to exceeding recommended dosages (Table 83. Because of this difference and others, acet- aminophen is considered separately later. Primary beneficial effects are pain relief, suppression of inflammation, and reduction of fever. Primary adverse effects are gastric ulceration, acute renal failure, and bleeding. Unfortunately, the selective inhibitors pose a greater risk for thrombotic events, and hence long- term use of these drugs is not recommended. Many anticancer drugs suppress bone marrow function and thereby decrease platelet production. Aspirin should be avoided because it causes irreversible inhibition of platelet aggregation. Combining acetaminophen with an opioid can produce greater analgesia than either drug alone (because acetaminophen and opioids relieve pain by different mechanisms). Because acetaminophen does not affect platelets, the drug is safe for patients with thrombocytopenia. Acetaminophen has important interactions with two other drugs: alcohol and warfarin (an anticoagulant). Combining acetaminophen with alcohol, even in moderate amounts, can result in potentially fatal liver damage. Acetaminophen also can increase the risk for bleeding in patients taking warfarin. The mechanism appears to be inhibition of warfarin metabolism, which causes warfarin to accumulate to toxic levels. Opioid Analgesics Opioids are the most effective analgesics available and hence are the primary drugs for treating moderate to severe cancer pain. With proper dosing, opioids can safely relieve pain in about 90% of cancer patients. Unfortunately, many patients are denied adequate doses, owing largely to unfounded fears of addiction. In addition to analgesia, they can cause sedation, euphoria, constipation, respiratory depression, urinary retention, and miosis. With continuous use, tolerance develops to most of these effects, with the notable exceptions of constipation and miosis. Continuous use also results in physical dependence, which must not be equated with addiction. Mechanism of Action and Classification Opioid analgesics relieve pain by mimicking the actions of endogenous opioid peptides (enkephalins, dynorphins, endorphins), primarily at mu receptors and partly at kappa receptors. Based on their actions at mu and kappa receptors, the opioids fall into two major groups: (1) pure (full) agonists (e. The pure agonists can be subdivided into (1) agents for mild to moderate pain and (2) agents for moderate to severe pain. In contrast, the agonist-antagonists act as agonists only at kappa receptors; at mu receptors, these drugs act as antagonists. Because their agonist actions are limited to kappa receptors, the agonist-antagonists have a ceiling to their analgesic effects. Furthermore, because of their antagonist actions, the agonist-antagonists can block access of the pure agonists to mu receptors, and can thereby prevent the pure agonists from relieving pain. Tolerance and Physical Dependence Over time, opioids cause tolerance and physical dependence. These phenomena, which are generally inseparable, reflect neuronal adaptations to prolonged opioid exposure. Some degree of tolerance and physical dependence develops after 1 to 2 weeks of opioid use. Put another way, tolerance is a state in which dosage must be increased to maintain the desired response. Accordingly, significant tolerance to one opioid confers a similar degree of tolerance to all others. Physical Dependence Physical dependence is a state in which an abstinence syndrome will occur if a drug is abruptly withdrawn. The intensity and duration of the abstinence syndrome are determined in part by the duration of drug use and in part by the half-life of the drug taken.