Ultram[R]er: (tramadol HCl) extended-release tablets: an oral once-daily formulation of tramadol.

INTRODUCTION ULTRAM ER, a nonscheduled centrally acting synthetic opioid analgesic, is the first US Food and Drug Administration (FDA)-approved, extended-release tramadol hydrochloride (manufactured by Biovail Corporation, Mississauga, Canada; distributed by PriCara[TM], Unit of Ortho-McNeil, Inc, Raritan, NJ) that provides once-daily dosing to manage moderate-to-moderately severe chronic pain in adults. Because it is not a nonsteroidal anti-inflammatory drug (NSAID), cyclooxygenase (COX)-2 inhibitor, or a scheduled opioid, ULTRAM ER provides an alternative to traditional treatment options. This article (t) provides an overview of the economic and physical burden of chronic pain in the United States, (2) examines variables that affect treatment options for chronic pain conditions, (3) discusses the safety and efficacy of ULTRAM ER, (4) outlines the rationale for choosing ULTRAM ER for appropriately selected patients, and (5) provides an overview of formulary considerations of ULTRAM ER in the management of chronic, noncancer-related pain. BURDEN OF CHRONIC PAIN According to the 2003 Americans Talk About Pain survey, chronic pain, which is defined as pain that "continues beyond the usual recovery period for an injury or illness, and may be continuous or come-and-go," has been estimated to affect 57% of Americans. (2) Of those suffering from chronic pain, 3 out of 5 have lived in a state of pain for more than 1 year. (2) Due to its high prevalence, chronic pain represents a major health problem that results in personal suffering, reduced productivity, and substantial healthcare costs. Of those living with chronic pain, 20% have had to take disability leave from work, 17% have had to change jobs or professions, and 13% have required help with daily activities such as bathing, dressing, or eating. (2) Chronic pain costs more than $100 billion per year in medical expenses, lost wages, and lost productivity. (3) A survey examining the burden of pain on employee health and productivity reported that pain was associated with decreases of 45% and 23%, respectively, in overall physical and mental health. (4) The most common noncancer-related chronic pain conditions include episodic migraine headaches, arthritis, back pain, and other musculoskeletal conditions (Figure 1), (5) and have resulted in a 13% loss in US workforce productivity, resulting in a $61.2 billion per-year loss in productive work time. (6) Osteoarthritis is a leading cause of disability in the United States, with an estimated annual cost of $7.11 billion in lost productive work time; 65.7% of that cost is due to chronic pain. (7) Chronic back pain, which affects approximately 30 million Americans, is the leading cause of inactivity in young adults and the cause of $28 billion of losses in worker productivity annually. (8) [FIGURE 1 OMITTED] Results of a study of 242 patients with noncancer-related chronic pain demonstrated that chronic pain significantly decreases overall quality of life, (9) and many patients with chronic pain experience depression, making it the most common comorbidity. (10) Chronic pain is also associated with anxiety and posttraumatic stress disorder," and many patients suffering from chronic pain experience poor sleep, which contributes to decreased quality of life. (12) Approximately 65% of people with chronic pain reported disrupted or nonrestorative sleep (13); the most frequent sleep complaints include delayed onset of sleep, frequent awakenings, decreased sleep duration, daytime fatigue, and nonrestorative sleep. (14) According to the National Survey of Self-care and Aging, more than 30% of participants reported arthritis-related sleep disruptions. (15) One third of adults in the United States experience nighttime pain and inability to sleep, and one third of those who reported nighttime pain specified that the pain was due to arthritis, according to the results of a Gallup survey conducted in the 1990s. (16) In a study of patients with chronic knee pain due to osteoarthritis (N=429), 31% reported problems with sleep onset, 81% reported problems with sleep maintenance, and 51% reported that early-morning awakenings occurred at least weekly. (17) Sleep disruption in people suffering from chronic pain may be caused by the extensive amounts of time these individuals spend in bed, which disrupts the physiologic rhythm of sleep. (14) According to a study of patients with chronic low back pain, greater pain intensity was associated with lower sleep satisfaction, less total sleep time, delayed onset of sleep, and more awakenings due to pain compared with controls. (18) In addition, pharmacologic treatments administered for chronic pain, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and some opioid analgesics, may alter sleep patterns, (19,20) thus adding to the complexity of managing pain in these patients. TREATMENT CONSIDERATIONS IN MANAGING CHRONIC PAIN Results of a survey conducted by the American Pain Society of 800 patients with moderate-to-severe chronic noncancer-related pain found that 59% of participants with ever-present pain felt that their pain was not under control, (21) suggesting that chronic pain remains inadequately treated despite the available treatment options. Because patients with chronic pain often have comorbid conditions, physicians must consider possible drug-drug interactions that analgesics may have with other medications being administered. Therefore, many factors should be considered when choosing an analgesic agent for an individual patient. The ideal analgesic therapy for chronic pain should combine around-the-clock efficacy with maximal tolerability and minimal long-term adverse effects, and no organ toxicity resulting from prolonged use (eg, detrimental effects to the heart, liver, kidneys, and gastrointestinal system). Current pharmacologic management of chronic pain includes the use of nonopioid analgesics (eg, nonselective NSAIDs, acetaminophen, and COX-2 inhibitors), scheduled opioid analgesics (eg, oxycodone and morphine), nonscheduled opioid analgesics (eg, tramadol), and adjuvant analgesics (eg, antidepressants and anticonvulsants) (Table 1). (22) Long-acting analgesics (ideally drugs that can be dosed once or at most twice daily) may be a valuable choice for treating chronic pain because they offer multiple potential advantages, including more consistent pain control (less frequent peak/trough fluctuation), improved nighttime pain control (less need to medicate at night), decreased analgesic gaps, and less clock-watching by patients in chronic pain. Abuse potential is another important consideration for analgesic selection both for the patient and the prescriber. Drugs with a history of low abuse potential are preferable. Another consideration is the scheduling status of an analgesic. Nonscheduled products allow for fewer patient visits, where appropriate. NONOPIOID ANALGESICS Nonopioid analgesics such as acetaminophen and NSAIDs are effective as single agents, or in combination with other agents for the treatment of mild-to-moderate chronic pain. One of the most widely used nonopioid analgesics is aspirin, which inhibits prostaglandin synthesis. The primary mechanism of action of acetaminophen, another commonly used nonopioid analgesic, remains unknown. Acetaminophen is generally safe and well-tolerated within the therapeutic dose range of up to 4000 mg/d; above this dose, renal and hepatic toxicities may occur. (24,25) Use of acetaminophen requires multiple dosing to achieve continuous pain relief, especially in osteoarthritis patients, which may result in noncompliance. (23) NSAIDs can be divided into 2 categories: nonselective and selective. Nonselective NSAIDs include aspirin, naproxen, ibuprofen, and others. The primary mechanism of action of aspirin and nonselective NSAIDs is the inhibition of COX-1, which mediates normal platelet function, renal blood flow, and protection of gastrointestinal mucosa, and of COX-2, which mediates inflammation, pain, and fever. (39) One limitation to NSAID use is the associated ceiling effect; that is, beyond a certain dosage, efficacy is not enhanced....