Drug Review 2009

From Giant Steps in Emergency Medicine 2009, sponsored by Sterling Healthcare and Giant Steps in Emergency Medicine

Joseph R. Lex Jr, MD, Associate Professor of Emergency Medicine, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA

Educational Objectives

The goal of this program is to improve management of patients treated in the emergency department (ED). After hear­ing and assimilating this program, the clinician will be better able to:

1.   Compare the efficacy of lacosamide to placebo in the treatment of partial complex seizures and diabetic neuro­pathic pain.

2.   Review the indications for use of romiplostim and eltrombopag in idiopathic thrombocytopenic purpura.

3.   Explain use of methylnaltrexone injection in the ED for opioid-induced constipation in patients receiving palli­ative care.

4.   Utilize clevidipine as an alternative to other agents (eg, esmolol, nicardipine) in the management of hyperten­sive emergencies in the ED.

5.   Discuss the use of the nonopioid pain treatment, tapentadol, and compare it to other pain relievers.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Lex and the plan­ning committee reported nothing to disclose. In his lecture, Dr. Lex presents information that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Lex was recorded at Giant Steps in Emergency Medicine 2009, held July 20-23, 2009, in San Diego, CA, and sponsored by Sterling Healthcare and Giant Steps in Emergency Medicine. The Audio-Digest Foundation thanks Dr. Lex and the sponsors for their cooperation in the production of this program.

Introduction: in last few years, several new drugs taken off market because of premature approval; explosion of clin­ical drug trial irregularities seen; exercise caution when looking at drug literature; Food and Drug Administration (FDA) issued guidelines to facilitate drug manufacturers’ promotion of off-label prescription drug use; drug manu­facturers not allowed to promote drugs for off-label uses, but physician allowed to use drug for any purpose deemed necessary; former editor of New England Journal of Medicine states no longer possible to believe most of clinical research published or to rely on judgment of trusted physicians or authoritative medical guidelines; olanzapine (Zyprexa)  —  linked to deaths of thousands of patients, especially elderly; also linked to thousands of cases of diabe­tes, especially in Latino population

Lacosamide (Vimpat): approved for adjunctive treatment of partial complex seizures and diabetic neuropathic pain (similar to gabapentin [Neurontin]); mechanism of action slow inactivation of voltage-gated sodium channels; study  —  double-blind; placebo-controlled; intention to treat; 25% dropout rate; end point percentage of patients with ³50% reduction of seizures; with placebo, fewer seizures seen in >1 of 5 patients; dose-related response £400 mg with lacosamide; difference in seizure reduction between 400 mg daily and placebo not impressive; those pro­moting drug state that drug reduces number of seizures by 50%, compared to placebo; adverse effects those seen with sodium-channel blockers; no effect on concomitantly administered antiepileptic drugs; study  —  for painful di­abetic neuropathy; open label; dose escalated weekly to maximum of 400 mg daily; 20-wk maintenance period, with participants allowed to stay on drug as long as desired; 68% completed maintenance period and elected to con­tinue; another 50% stayed until study terminated; 90% elected to continue drug at study termination; similar num­bers seen with gabapentin; significant reduction in Likert pain score and neuropathic pain scales; concluded that drug moderately successful at reducing seizures as secondary agent, but need to treat 5 patients for 1 patient to have 50% reduction; moderately successful at reducing painful diabetic neuropathy; gabapentin effect  —  popularity based on unacceptable science published in medical journal supplements (not peer reviewed) and paid for by drug company

Romiplostim (Nplate): for idiopathic thrombocytopenic purpura (ITP); most patients with ITP have platelet destruc­tion; 75% have normal or reduced production also, but thrombopoietin (TPO) levels normal; short-term treatments for increasing number of platelets include steroids, intravenous immunoglobulin (IVIG), and IV anti-D antibody; long-term treatments include splenectomy and other drugs; all work by decreasing platelet destruction; 2 drugs work by increasing platelet production (stimulating bone marrow); TPO-stimulating protein; approved for use only if poor response to steroids, IVIG, and splenectomy seen or when thrombocytopenia increases risk for bleeding; dose weekly; given subcutaneously (SQ); not used in attempt to normalize platelet counts; unable to prescribe, un­less enrolled in Network of Experts Understanding and Supporting Nplate and patients (NEXUS) program; effec­tive for primary end point of increase in platelets >50 000/mL and sustained over 2 yr (2.5 yr); also studied in hepatitis C-induced thrombocytopenia; question of whether patient-oriented outcome or disease-oriented outcome; 95% of patients report ³1 adverse event; serious adverse events seen in one-third of patients

Eltrombopag (Promacta): TPO mimic; stimulates bone marrow to increase production of platelets; given orally; ef­fective for primary end point of platelet numbers; dose-related effect; »80% of patients achieve platelet count >50,000/mL after using drug for some time; sustained effect seen over 2.5-yr study period; side effects not yet known due to limited exposure to drug (<600 patients treated); no studies to show whether drug results in shorter hospital stay, fewer admissions to hospital, or adds to years of life; rebound thrombocytopenia when patient discon­tinues drug, with implication for thromboembolic complications; stimulates entire bone marrow, with increase in blast counts and reticulin formation in bone itself; expensive

Diclofenac: pain patch (Flector); also formulated as eye drops; banned for veterinary use in India (3 species of vul­tures almost became extinct due to renal failure from feeding on carcasses of cattle treated with diclofenac); anti-in­flammatory; patch applied twice daily to painful area due to minor sprains, strains, and contusions; topical nonsteroidal anti-inflammatory drugs (NSAIDs) have <5% of serum concentration of oral NSAIDs; meniscus and cartilage concentrations 4 to 7 times higher than with oral administration, and tendon sheath concentration several hundred times higher (disease-oriented outcomes); patient-oriented outcomes  —  topical NSAIDs reduce pain scores by »50% at 2 wk in »20% of patients with chronic pain (same as oral NSAIDs); less efficacious than oral NSAIDs in patient with osteoarthritis; acute pain  —  reduces pain scores by 50% in 25% of patients after acute musculoskeletal injury (same as oral NSAIDs); intuitively safer; available in Europe for years; case reports of gas­trointestinal (GI) bleeding; expensive; patients who obtain most relief those with shin splints; exercise caution; use only in specific instances (eg, elderly patient, if concerned about renal function and GI bleeding); reduces risk, but pain relief moderate; no study showing advantage of NSAID over acetaminophen for any musculoskeletal injury; amount of pain relief and decrease in swelling same, despite anti-inflammatory properties; same return to full activ­ity and more side effects, but lower cost with acetaminophen

Methylnaltrexone (Relistor): off-label use recommendation in emergency department (ED); opioid-induced consti­pation, nausea, and vomiting caused by stimulation of same receptors responsible for pain relief; pain from consti­pation one of top reasons for presenting to ED for patients in hospice or respite care; peripherally acting mu opioid receptor antagonist similar to naltrexone; methyl arm prevents crossing of blood-brain barrier; reverses opioid ef­fects in gut and leaves pain relief in brain and central nervous system (CNS); reduces constipating effects of opioid without reducing analgesia; indicated for treatment of opioid-induced constipation in patients with advanced illness receiving palliative care who are poorly responsive to standard laxative therapy (FDA approval); >50% of patients had bowel movement (BM) within 4 hr of first dose; of those who responded, median time to BM 30 min from time drug given; placebo response »15%; potential use in ED seen; recommended SQ injections every other day; most common adverse effect abdominal pain (£30%); also flatulence, nausea, and dizziness; cost $40/injection

Clevidipine (Cleviprex): IV calcium-channel blocker; promoted as alternative to esmolol and nicardipine in control­ling hypertensive emergencies in ED; ultra short-acting (similar to esmolol; 15-min duration); no association with bradycardia or bronchospasm (similar to esmolol); no dosing change needed for renal or hepatic impairment; lipid emulsion (in eggs and soy); need to overlap infusion with oral drug; trials  —  perioperative studies (not ED studies); Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial and Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) trial; Evaluation of the Effect of Ultra-Short-Acting Clevidipine in the Treatment of Patients with Severe Hyperten­sion (VELOCITY) trial for ED; Seventh Report of the Joint National Committee on Prevention, Detection, Evalua­tion, and Treatment of High Blood Pressure (BP; JNC)7  —available online; states that no evidence to suggest that failure to aggressively lower BP in ED associated with any increased short-term risk to patient who presents with severe hypertension (HTN) and that term “urgency” has led to overly aggressive management of many patients with severe uncomplicated HTN; article stated that clevidipine (IV dihydropyridine calcium-channel blocker) safe and effective for treatment of patient with acute severe HTN; VELOCITY trial  —  subjects ³18 yr of age with sys­tolic BP of ³180 mm Hg or diastolic BP of ³115 mm Hg; assessed for end-organ injury but not inclusion require­ment; end-organ damage seen included renal dysfunction, proteinuria, hematuria, and left ventricular hypertrophy (LVH) on electrocardiography (ECG); 117 subjects without end-organ injury and 24 subjects with end-organ injury (mostly LVH on ECG and renal dysfunction); both groups treated in same manner; found effective; patient-specific target systolic BP reduction within range of 20 to 40 mm Hg; able to alter target after 30 min of treatment, then transition to oral agent; within 30 min of starting drug, 89% achieved BP in target range (roughly 20% reduction in BP); very safe; not compared to esmolol, nicardipine,  nitroprusside, labetalol, or fenoldopam; Cochrane database  —  no randomized controlled trial (RCT) evidence demonstrating that antihypertensive drugs reduce mor­tality and morbidity in patient with hypertensive emergency; insufficient RCT evidence to determine which drug or drug class most effective in reducing morbidity or mortality; cost $180 per 25-mg vial

Granisetron transdermal system (Sancuso): patch; serotonin  —5-hydroxytryptamine (5-HT); monoamine neurotrans­mitter synthesized in CNS and gut enterochromaffin cells; chemotherapy causes release of serotonin in GI tract and brainstem; increase in 5-HT leads to nausea and vomiting; 5-HT3 antagonists or setrons  —  reduce activity of vagus nerve; act on other parts of brain to reduce vomiting; no effect on dopamine or muscarinic receptors; no effect on motion sickness; not effective for peripheral causes of nausea and vomiting; ondansetron (Zofran) used for nausea and vomiting; several setrons on market; still unknown which medication best, safest, and most effective in patient with undifferentiated vomiting in ED; generic ondansetron now available; generic granisetron (Kytril) also avail­able; granisetron patch applied 2 days before chemotherapy; lasts 5 to 7 days; patch expensive; regadenoson (Lexiscan) promoted as replacement for adenosine stress test

Desvenlafaxine (Pristiq): metabolite of venlafaxine (Effexor) which came off-patent recently; serotonin-norepineph­rine reuptake inhibitor; approved for major depression; when compared to placebo, only »50% of patients had 50% response rate, and only about one-third had remissions (standard for antidepressants); New England Journal of Medicine article on antidepressant trials  —  of 74 trials on antidepressants submitted to FDA, only 37 viewed posi­tive and published and 1 viewed positive but not published; 22 viewed negative and not published; 11 negative or questionable but made to appear positive; publication bias huge problem; difficult to have negative studies pub­lished; looking at all published literature on antidepressants, 94% positive, even though only 50% of studies sub­mitted to FDA positive; concept of atypical antidepressants misnomer; actually new generation, not atypical; clozapine (Clozaril)  —  only atypical antidepressant; for schizophrenia; causes bone marrow suppression; minimal difference in efficacy between antidepressants and placebo; no difference in moderate depression and small differ­ence in severe depression; huge placebo effect

Tapentadol (Nucynta): nonopioid pain treatment; centrally acting analgesic; agonist at mu opioid receptor; potency between morphine and tramadol; percentage of patients experiencing ³50% pain relief after third molar extraction  —  400 mg ceiling dose of ibuprofen for pain relief (slightly more anti-inflammatory effect if >400 mg); with morphine, 60 mg (10% bioavailability; no ceiling effect); 60 mg of oral morphine equivalent to »6 mg SQ or IV; at 200 mg of tapentadol, 88% obtained pain relief; time until effect seen  —  8 hr for lower doses; 1.5 hr for higher doses (same as ibuprofen); adverse effects  —  49% of participants on placebo had adverse effect (fewer with ibuprofen); dose-related adverse effect seen with tapentadol (higher dose, higher rate of adverse effects); with 200 mg, adverse effects in 92%); maximum pain relief seen with 200 mg; company attempted to market drug without schedule 2 license (wanted schedule 3), but FDA considered it schedule 2

CereTom: portable computed tomography scanner for head and neck; on wheels; lead shielding; heavy (740 lb); ex­pensive; requires 2 hr to warm up

Conclusions: romiplostim and eltrombopag for appropriate ITP patients; methylnaltrexone for palliative care and possibly for off-label use in ED or very specific patients; no niche yet for clevidipine; consider granisetron trans­dermal patch for vomiting from chemotherapy

Suggested Reading

Aronson S et al: The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg 107:1110, 2008; Bussel JB et al: Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113:2161, 2009; Erratum in: Blood 113:4822, 2009; Chappell D et al: Methylnaltrexone for opioid-induced consti­pation in advanced illness. N Engl J Med 359:1071, 2008; Kleinert R et al: Single dose analgesic efficacy of tapent­adol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesth Analg 107:2048, 2008; No authors listed: A diclofenac patch (Flector) for pain. Med Lett Drugs Ther 50:1, 2008; No au­thors listed: A granisetron patch (sancuso). Med Lett Drugs Ther 50:103, 2008; No authors listed: Desvenlafaxine for depression. Med Lett Drugs Ther 50:37, 2008; No authors listed: Lacosamide for epilepsy. Med Lett Drugs Ther 51:50, 2009; No authors listed: Tapentadol (Nucynta)--a new analgesic. Med Lett Drugs Ther 51:61, 2009; Erratum in: Med Lett Drugs Ther 51:68, 2009; No authors listed: Two new drugs for chronic ITP. Med Lett Drugs Ther 51:10, 2009; Panzer S et al: Eltrombopag in chronic idiopathic thrombocytopenic purpura. Lancet 373:607, 2009; Erratum in: Lancet 373:1606, 2009; Pollack CV et al: Clevidipine, an intravenous dihydropyridine calcium channel blocker, is safe and effective for the treatment of patients with acute severe hypertension. Ann Emerg Med 53:329, 2009.