Phase 3 Study Compares Tapentadol Extended Release Tablets to Placebo in Patients With Chronic Low Back Pain

RARITAN, N.J., Sept. 27 /PRNewswire/ -- Phase 3 safety and efficacy data comparing tapentadol extended release (ER) tablets, an investigational pain medication, to placebo in patients with moderate to severe chronic low back pain have been published online by Expert Opinion on Pharmacotherapy. In addition, this study compared oxycodone controlled-release (CR) to placebo as an active control.

Tapentadol ER vs. Placebo

The study demonstrated that a significantly higher percentage of patients receiving tapentadol ER tablets achieved at least a 30 percent improvement in pain intensity compared to placebo (39.7 percent vs. 27.1 percent, respectively; nominal p<0.001), and a significantly higher percentage of patients receiving tapentadol ER achieved at least a 50 percent improvement in pain intensity compared to placebo (27 percent vs. 18.9 percent; nominal p=0.016), indicating a clinically significant improvement in pain intensity.

To measure perceived change in overall health status, patients were asked to report their pain twice during the maintenance period and once at the end of study treatment. Results of this patient global impression of change (PGIC) analysis indicated that patients receiving tapentadol ER tablets showed a statistically significant improvement compared with placebo (nominal p<0.001).  

Primary endpoints for the study were the changes in average daily pain intensity from baseline (11-point numerical rating scale) to the last week of the maintenance period and over the study's entire 12-week maintenance period. Tapentadol ER significantly reduced average pain intensity compared with placebo at Week 12 of the maintenance period (tapentadol ER, -2.9 mean change [2.66 standard deviation]; placebo, -2.1 [2.33]; nominal p<0.001) and for the overall maintenance period (tapentadol ER, -2.8 [2.50]; placebo, -2.1 [2.20]; p<0.001).

The percentage of patients who completed the study in the placebo, tapentadol ER, and oxycodone CR groups was 47.6 percent, 52.2 percent and 40.5 percent, respectively. The primary reasons for treatment discontinuation in the two active treatment groups were adverse events (tapentadol ER, 16.7 percent; oxycodone CR, 32.3 percent; placebo, 4.7 percent) and lack of efficacy in the placebo group (tapentadol ER, 5.7 percent; oxycodone CR, 2.7 percent; placebo, 20.7 percent).

The rate of patient discontinuations from the study due to all treatment-emergent adverse events (TEAEs) was 16.7 percent for patients in the tapentadol ER group and 4.4 percent for the placebo group. For all gastrointestinal-related TEAEs, the discontinuation rate for patients in the tapentadol ER group was 5.3 percent versus 1.3 percent for patients in the placebo group. Specifically, 1.6 percent of tapentadol ER patients discontinued due to nausea, 1.3 percent because of constipation, and 2.5 percent due to vomiting.

The incidence of patients who reported at least one TEAE was 59.6 percent for placebo and 75.5 percent for tapentadol ER. The percentages of tapentadol ER patients experiencing common TEAEs (reported by >10 percent in any group of the study) included 20.1 percent with nausea, 13.8 percent with constipation, 19.8 percent with headache, 9.1 percent with vomiting, 11.9 percent with dizziness, 7.2 percent with pruritus, and 13.2 percent with somnolence.

"The study provides important data regarding the safety and efficacy of tapentadol ER," said Dr. Bruce Moskovitz, Therapeutic Area Leader for Pain, Ortho-McNeil-Janssen Scientific Affairs, LLC. "We are pleased that results show tapentadol ER may effectively relieve moderate to severe chronic low back pain while demonstrating a favorable tolerability profile."

In this study, patients were randomized in a 1:1:1 ratio to receive controlled, adjustable doses twice a day of tapentadol ER (100-250 mg), oxycodone HCl CR (20-50 mg) or placebo during a 15-week double-blind treatment period. There were 981 patients initially randomized in the study, though 965 patients (placebo, n=319; tapentadol ER, n=318; oxycodone CR, n=328) received at least one dose of study medication and were evaluable for safety. (Data were excluded for 14 patients who did not take study medication and two patients who were randomized twice.)

Oxycodone CR vs. Placebo

The oxycodone CR arm was compared to placebo as an active control. Results showed significant reductions in average pain intensity for the oxycodone CR group compared with the placebo group at Week 12 (oxycodone CR, -2.9 [2.52]; placebo, -2.1 [2.33]; nominal p<0.001) and over the entire maintenance period (oxycodone CR, -2.9 [2.36]; placebo, -2.1 [2.20]; nominal p<0.001). In the oxycodone CR group, the percentage of patients with at least a 30 percent and at least a 50 percent improvement did not differ significantly from placebo (30.4 percent, p=0.365, and 23.3 percent, nominal p=0.174, respectively for oxycodone CR).

The rate of oxycodone CR patient discontinuations from the study due to all TEAEs was 31.7 percent. For gastrointestinal-related TEAEs, the discontinuation rate for patients in the oxycodone CR group was 18.3 percent. Discontinuation rates for specific gastrointestinal-related TEAEs in this group included 11.3 percent due to nausea, 4.3 percent due to constipation, and 7.0 percent due to vomiting.

The incidence of oxycodone CR patients who reported at least one treatment-emergent adverse event (TEAE) was 84.8 percent. The percentages of oxycodone CR patients experiencing common TEAEs included the 34.5 percent with nausea, 26.8 with constipation, 16.8 percent with headache, 19.2 percent with vomiting, 17.1 percent with dizziness, 16.8 percent with pruritus, and 16.2 percent with somnolence.

Study researchers also conducted additional secondary statistical analyses, which may be found in the full article, published in Expert Opinion on Pharmacotherapy and accessible online at:  http://informahealthcare.com/doi/abs/10.1517/14656566.2010.497720?prevSearch=allfield%253A%2528tapentadol%2529&searchHistoryKey.

Low back pain is a common chronic pain condition and affects approximately 26 percent of adults in the United States. Current treatment includes the use of long-acting opioid analgesics for the relief of moderate to severe chronic pain. These treatments are associated with high incidences of side effects that can cause some patients to discontinue their treatment.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) and Grunenthal GmbH, conducted this study, which J&JPRD has included as part of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of moderate to severe chronic pain in patients 18 years of age or older. FDA currently is reviewing this application and, if approved, PriCara®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., will market tapentadol ER in the United States.

About tapentadol

Tapentadol is a centrally acting oral analgesic that binds to mu-opioid receptors and inhibits norepinephrine re-uptake. Although the exact mechanism of action is not known, these two mechanisms, which affect established pain pathways, are thought to be responsible for pain relief with tapentadol. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA® (tapentadol immediate release) was approved by the FDA on November 20, 2008, and is available by prescription only for the relief of moderate to severe acute pain in patients 18 years of age or older. On December 1, 2009, J&JPRD submitted its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tapentadol extended release (ER) tablets for the management of moderate to severe chronic pain in patients 18 years of age or older. The tapentadol ER tablet formulation is designed to provide a high degree of mechanical resistance, such as to crushing or chewing. The NDA filing is part of the ongoing commitment of J&JPRD and PriCara® to bring new and innovative products to patients and physicians for the treatment and management of pain.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA® (tapentadol)

Contraindications

Like other drugs with mu-opioid agonist activity, NUCYNTA® is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.  NUCYNTA® is contraindicated in patients who have or are suspected to have paralytic ileus.  NUCYNTA® is also contraindicated in patients currently using or within 14 days of using monoamine oxidase inhibitors (MAOIs) due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

Warnings & Precautions

Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.  NUCYNTA® should be administered with caution to the elderly, debilitated patients, and patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma.  In such patients, even usual therapeutic doses of NUCYNTA® may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA® should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.  

Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma or death may result if these drugs are taken in combination with NUCYNTA®. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.

Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention.  Therefore, NUCYNTA® should not be used in patients susceptible to the effects of raised cerebrospinal fluid pressure such as those with head injury and increased intracranial pressure.  Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness.  NUCYNTA® should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

NUCYNTA® is a mu-opioid agonist and is a Schedule II controlled substance.  Such drugs are sought by drug abusers and people with addiction disorders.  Diversion of Schedule II products is an act subject to criminal penalty.  NUCYNTA® can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse.  All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction.  NUCYNTA® may be abused by crushing, chewing, snorting or injecting the product.  These practices pose a significant risk to the abuser that could result in overdose and death.

Experience with NUCYNTA® overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of NUCYNTA® is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

Patients should be cautioned that NUCYNTA® may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.  This is to be expected especially at the beginning of treatment, at any change of dosage as well as in combination with alcohol or tranquilizers.

NUCYNTA® has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies.  NUCYNTA® should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.

The development of a potentially life-threatening serotonin syndrome may occur with use of SNRI products, including NUCYNTA®, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, and with drugs which impair metabolism of serotonin (including MAOIs).  Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Withdrawal symptoms may occur if NUCYNTA® is discontinued abruptly.  These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA®.

Pregnancy Category C.  There are no adequate and well-controlled studies of NUCYNTA® in pregnant women.  NUCYNTA® should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus. NUCYNTA® is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking NUCYNTA® should be monitored for respiratory depression. NUCYNTA® should not be used during breastfeeding.

NUCYNTA® is not recommended in patients with severe renal or hepatic impairment.  NUCYNTA® should be used with caution in patients with moderate hepatic impairment.  Like other drugs with mu-opioid agonist activity, NUCYNTA® may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Adverse Events

The most common adverse events are nausea, dizziness, vomiting, somnolence and headache. To see the NUCYNTA® full prescribing information, go to http://www.nucynta.com/nucynta/assets/Nucynta-PI.pdf.

PriCara®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

PriCara®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is a major health care company in the United States dedicated to the needs of primary care providers who serve a vital role on the frontline of medicine. For more information about the company, please visit www.PriCara.com.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., (J&JPRD) is a wholly owned subsidiary of Johnson & Johnson, the world's most broadly-based producer of health care products. J&JPRD is headquartered in Raritan, N.J., and has facilities throughout Europe, the United States and Asia. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas, including CNS, Internal Medicine and Oncology, to address unmet medical needs worldwide. More information can be found at www.jnjpharmarnd.com.  

SOURCE PriCara(R), Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.