New drugs: tapentadol hydrochloride, tolvaptan, and benzyl alcohol.

Analgesic Tapentadol hydrochloride (Nucynta—PriCara) is a centrally acting analgesic that acts via two mechanisms to relieve pain. Like the opioid analgesics (e.g., morphine, oxycodone), it is a muopioid receptor agonist, but unlike these agents, it also inhibits norepinephrine reuptake. The pharmacological actions of tapentadol are most similar to those of tramadol (e.g., Ultram), which has an opioid agonist action and also inhibits norepinephrine and serotonin reuptake. However, the opioid agonist action of tapentadol is stronger than that of tramadol, and the new drug also has a greater potential for dependence and abuse. This risk is reflected by the inclusion of tapentadol in Schedule II under the provisions of the Controlled Substances Act, as are the opioid analgesics, whereas tramadol is not a controlled substance. Tapentadol is supplied in an immediate-release tablet formulation (a controlled-release formulation is under development) and has been approved for the relief of moderate to severe acute pain in patients 18 years or older. Both tramadol and oxycodone are also available in controlled-release formulations (e.g., Ultram ER, OxyContin) that are used over longer periods of time in the management of chronic pain. The indication for certain of these formulations (Ultram ER, OxyIR) is for the relief of moderate to moderately severe pain. The effectiveness of tapentadol has been demonstrated in studies in which it was compared with placebo and, to a more limited extent, with oxycodone. The percentages of patients who showed reduction in pain intensity of 30% or greater, or 50% or greater, were significantly higher in the patients treated with the new drug compared with placebo. The results of one study suggest that the analgesic benefit of tapentadol in a dose of 100 mg is similar to that provided by oxycodone in a dose of 15 mg. The primary risk of the opioid agonists including tapentadol is respiratory depression, and these agents are contraindicated in patients with considerable respiratory depression or with acute or severe bronchial asthma or hypercapnia, in unmonitored settings, or in the absence of resuscitative equipment. Caution must be exercised when tapentadol is used in patients with less serious underlying pulmonary problems, as well as in elderly or debilitated patients who are at greater risk of experiencing impaired pulmonary function. Opioid analgesics may increase cerebrospinal fluid pressure as a result of respiratory depression, and they must be used with caution in patients with head injury, intracranial lesions, or other sources of increased intracranial pressure. Like the other opioid agonists, tapentadol is contraindicated in patients with paralytic ileus. Because these agents may cause spasm of the sphincter of Oddi, caution must be exercised when they are used in patients with biliary tract disease, including acute pancreatitis. The adverse events most often reported in the clinical studies of tapentadol include nausea (30%), vomiting (18%), constipation (8%), dizziness (24%), and somnolence (15%). In the studies in which some patients received oxycodone, the incidence of gastrointestinal events was lower with tapentadol. Because of its central nervous system (CNS) depressant action, patients should be advised that tapentadol may impair the mental and/or physical abilities required for potentially hazardous tasks such as driving or operating machinery. The concurrent use of other CNS depressants, including alcoholic beverages, may result in an additive depressant effect, and consideration should be given to reducing the dosage of the agents implicated in such interactions. Patients with seizure disorders were excluded from the clinical studies of tapentadol, and the new drug must be used with caution in patients with a history of seizures or who are otherwise at greater risk of these problems. A more prominent warning regarding the risk of seizures is included in the labeling for tramadol, but insufficient data are available comparing the two drugs with respect to this risk. Tapentadol has an abuse potential that is considered similar to that of hydromorphone (e.g., Dilaudid), and it is classified in Schedule II. Although concerns about addiction and abuse should not prevent the proper management of pain, patients should be informed about these risks, and appropriate cautions regarding the use of tapentadol should be observed. Tapentadol is classified in Pregnancy Category C and should only be used during pregnancy if the anticipated benefit outweighs the risk to the fetus. The drug should not be used in women during and immediately before labor and delivery or in women who are breast-feeding. The effectiveness and safety of the new drug in patients younger than 18 years have not been established. Serotonin syndrome has been reported infrequently in patients treated with medications that inhibit reuptake of serotonin and/or norepinephrine. The risk is increased by the concurrent use of serotonergic drugs such as selective serotonin reuptake inhibitors (e.g., fluoxetine [e.g., Prozac]), serotonin and norepinephrine reuptake inhibitors (e.g., venlafaxine [e.g., Effexor]), tricyclic