Student Forum Tapentadol-ER for the Treatment of Diabetic Peripheral Neuropathy Gina Games, Amber Hutchison With the prevalence of diabetes mellitus (DM) increasing, pathologic complications such as diabetic peripheral neuropathy (DPN) are also becoming more common. Of those diagnosed with DM, 10% to 20% of patients suffer from painful DPN. Until recently, only pregabalin and duloxetine possessed Food and Drug Administration (FDA) approval for this condition. However, FDA recently approved tapentadol-ER [extended release] (Nucynta ER) for painful DPN. Tapentadol-ER is an opioid analgesic commonly used for the treatment of moderate-to-severe chronic pain that contains a unique dual mechanism acting as both a weak mu-opiod receptor agonist and norepinephine-reuptake inhibitor. It is by way of this unique dual mechanism that allows for effective analgesic effects with increased tolerability. This new FDA approval provides an additional therapeutic option to treat DPN in symptomatic patients. Key Words: Diabetes mellitus, Diabetic peripheral
neuropathy, Geriatric, Nucynta ER, Tapentadol ER Abbreviations: DM = Diabetes mellitus, DPN = Diabetic
peripheral neuropathy, ER = Extended release, MOR-NRI = mu-opiod receptor agonist-norepinephrine reuptake inhibitor, NRS = Numerical rating scale, SAE = Serious adverse event, SNRI = Serotonin-norepinephrine reuptake inhibitor, SSRI = Selective-serotonin reuptake inhibitor, TCA = Tricyclic antidepressant, TEAE = Treatment-emergent adverse event. Consult Pharm 2013;28:672-5.
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Background With more patients being diagnosed with diabetes mellitus (DM), pathological complications of DM are becoming more common. These complications include diabetic peripheral neuropathy (DPN).1-3 DPN has become the most common neuropathic syndrome seen in patients with DM, affecting up to 50% of patients.1 The estimated global prevalence of DM by 2030 will be 472 million individuals, suggesting that as many as 236 million patients may be affected by DPN.4 While the progression of DPN may be controlled with proper management of risk factors and glycemic control, the nociceptive and neuropathic pain associated with DPN is often chronic and difficult to manage.1-2,4 Approximately 10% to 20% of diabetic patients report painful DPN, resulting in increased morbidity, mortality, and substantial health care costs.1,4 Painful DPN is characterized as a burning, tingling, or aching sensation commonly affecting the lower limbs and typically worsening at night.2,4 The etiological cause of painful DPN is multifactorial, involving both central and peripheral mechanisms.4 Because of the complexity of the disease, medications with varying mechanisms of action may be needed to combat the refractory pain associated with DPN and to decrease the toxicity associated with its treatments.2 Current medications prescribed for painful DPN include tricyclic antidepressants (TCAs), anticonvulsants, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), opiates and opiatelike medications, and topical analgesics.2,5 While many medications can be recommended, until recently only pregabalin and duloxetine have received Food and Drug Administration (FDA) approval for DPN.2,5 Now, tapentadol ER [extended release] (Nucynta ER), a schedule II opioid analgesic commonly used for moderateto-severe chronic pain, has received FDA approval as the first and only opioid approved for symptomatic treatment of DPN, giving health care professionals an additional therapeutic choice.6
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Tapentadol-ER for the Treatment of Diabetic Peripheral Neuropathy
Pharmacology Profile While the exact mechanism of action is not clearly understood, preclinical trials of tapentadol ER demonstrate the analgesic effects resulting from the dual mechanism of μ-opioid receptor agonistic and norepinephrine reuptake-inhibitor activity (MOR-NRI).7-9 This distinct dual mechanism of action is suggested to represent a new pharmacological class: MOR-NRI.8 Tapentadol ER is considered a weak μ-opioid receptor-agonist, having an 18-fold decrease in receptor affinity compared with morphine.8 Despite the decrease in affinity, tapentadol ER only produced a two- to three-fold decrease in analgesic effects in animal studies.8 The analgesic effect can be explained by the synergistic interaction of the dual mechanism. The norepinephrine reuptake inhibition works by acting on the α-2 receptor located on the noxious nerve fibers in the spinal cord and central nervous system, inhibiting the transmission of pain impulses.7 The dual mechanism of tapentadol allows for potent analgesic effects that combat the complex pathology of neuropathic pain. Tapentadol ER preparation was developed to provide sufficient pain relief with the convenience of twice-daily dosing. It is available in 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets.6 The starting dose of tapentadol ER for opioid-naive patients is 50 mg twice daily, titrated to an effective and tolerable dose of 100 mg to 250 mg twice daily, with a maximum dose of 250 mg twice daily.8 The oral bioavailability of tapentadol ER is 32%, a result of extensive first-pass metabolism.6-8 The maximum serum concentration of tapentadol ER is increased by 17% when taken with a high-fat, high-calorie breakfast, but may be administrated without regard to meals.6,8 Peak serum concentrations occur three to six hours after administration, with steady-state concentrations achieved after the third dose.6 The parent tapentadol-ER drug is the active formulation, with 97% of the molecule metabolized by O-glucuronidation, resulting in its inactivation.6-8 The extensive hepatic metabolism of tapentadol ER accounts for the dose adjustments in hepatic impairment, extending the duration of administration to every 24 hours, with moderate hepatic impairment (Child-Pugh Score 7 to 9). It is subsequently contraindicated in severe hepatic
impairment.6 Tapentadol ER and its metabolites are excreted (99%) by the kidneys; regardless, no dose adjustments are required for renal impairment.6 Additional counseling points are located in Table 1.
Therapeutic Efficacy, Safety, and Tolerability The efficacy and safety of tapentadol ER for painful DPN has been evaluated by two DPN studies. Both studies included patients 18 years of age and older with either type 1 or type 2 DM and painful DPN for at least six months, with a pain-intensity score of at least 5 on an 11-point numerical rating scale (NRS). The studies consisted of two phases: a three-week, open-label phase during which all patients were titrated to an effective and tolerable tapentadol ER dose; and a 12-week, double-blind maintenance phase during which patients were randomized to either continue with their current tapentadol ER regimen or begin matching placebo. The primary endpoint analyzed was the change in average pain intensity.6,9 The first study was a randomized-withdrawal, placebo-controlled trial. A total of 591 patients entered into the open-label phase. Subsequently, 389 patients who achieved at least a one-point reduction in the NRS were randomized (1:1) for the maintenance phase. The age of the randomized study participants ranged from 29 to 87 (mean = 60 years).9 The second study was a doubleblind, parallel-group, randomized, placebo-controlled withdrawal trial. A total of 459 patients entered into the open-label phase, and 320 patients were randomized (1:1) for the maintenance phase. The age of the randomized study participants ranged from 28 to 83 years (mean = 59 years).9 Both studies reported that approximately twothirds of participants were opioid-naive.8,9 Both studies concluded tapentadol ER provided a statistically significant improvement of pain intensity compared with the placebo. During the open-label period, 60.5% of patients reported at least a 30% reduction in pain intensity, with 34.9% of patients reporting at least a 50% reduction in pain intensity. For the maintenance phase, 53.6% of patients randomized to the tapentadol ER treatment reported at least a 30% improvement by the end of
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Student Forum
Table 1. Counseling Points for Use with Tapentadol ER • Tapentadol ER must be dispensed with an FDA-approved medication guide. • Abuse Potential: Tapentadol ER is a schedule II controlled substance that is subject to abuse. • Life-threatening Respiratory Depression: Discuss risk with patients, explaining that the risk is greatest when first starting tapentadol ER or with an increase in dose. Special precaution should be taken with elderly patients because of an increased risk of respiratory depression. • Risks from Concomitant Use of Alcohol and other CNS Depressants: Inform patients about potentially serious additive effects (i.e., respiratory depression) if tapentadol is used with other CNS depressants. • Hypotension: Tapentadol ER may cause syncope and orthostatic hypotension. Patients should be advised to carefully rise from a sitting or lying position. • Seizures: Tapentadol ER could cause seizures if patients are at an increased risk for seizures or have epilepsy. • Important Administration Instructions: Tapentadol ER should not be cut, crushed, chewed, or dissolved. Source: Reference 6. Abbreviations: CNS = Central nervous system, ER = Extended release, FDA = Food and Drug Administration.
the 12-week maintenance phase. The least squares mean difference for the average change in pain-intensity score was statistically significant at 1.3 (95% confidence interval -1.70 to -0.92; P < 0.001).8,9 The incidence of treatment-emergent adverse events (TEAE) was 70.9% in the tapentadol ER study arm and 51.8% in the placebo study arm, with the most common side effects including nausea, anxiety, diarrhea, and dizziness. Most TEAEs reported were mild-to-moderate in intensity. Participant discontinuation was 20.1% in the open-label period, and 11.2% and 5.7% during the 12-week double-blind period for tapentadol ER and placebo, respectively. The most common TEAEs resulting in discontinuation included gastrointestinal (GI) adverse effects.9 Tapentadol ER has demonstrated an improved GI tolerability, compared with similar extended-release opioids.8 This increased tolerability is likely explained by the decreased affinity for the μ-opioid receptor.6-9 The incidence of treatment-emergent serious adverse
674
events (SAEs) was 5.1% in the tapentadol ER study arm and 1.6% in the placebo study arm. Most SAEs were determined to be unrelated to tapentadol ER.9
Conclusion With the rising incidence of DM and its associated complication of DPN, the utilization of medication to combat the chronic nociceptive pain will become more common.1-3 The FDA approval of tapentadol ER for the symptomatic treatment of painful DPN provides an additional therapeutic option with a unique mechanism of action.6 Tapentadol ER has proven safe and effective for the symptomatic treatment of DPN. As a result of the dual mechanism, studies suggest tapentadol ER may be particularly useful for complex pain encompassing both nociceptive and neuropathic pain components such as in DPN.6,9
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Tapentadol-ER for the Treatment of Diabetic Peripheral Neuropathy
The Consultant Pharmacist publishes a Student Forum column to encourage student pharmacists to publish articles on geriatric pharmacotherapy. It is an opportunity for them to discuss recently published research or regulatory findings on medications, brief reviews of newly approved medications with potential use in elderly patients, or new uses or findings regarding approved medications relevant to the elderly population. Submissions may represent research, opinion, or analysis. Manuscripts submitted for this section have at least one pharmacy student author and must be coauthored by a pharmacy school faculty mentor. H. Edward Davidson, PharmD, MPH Editor-in-Chief [email protected]
Gina Games is a 2013 PharmD candidate, Auburn University Harrison School of Pharmacy, Auburn, Alabama. Amber Hutchison, PharmD, BCPS, is assistant clinical professor, Auburn University Harrison School of Pharmacy, Auburn, Alabama. For correspondence: Amber Hutchison, PharmD, BCPS, Auburn University Harrison School of Pharmacy, 1321 Walker Building (4201F), Auburn, AL 36849; Phone: 334-844-8401; Fax: 334-8444410; E-mail: [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2013 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2013.672
References 1. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes 2005;23:9-15. 2. Lindsay TJ, Rodgers BC, Savath V et al. Treating diabetic peripheral neuropathic pain. Am Fam Physician 2010;82:151-8. 3. Centers for Disease Control and Prevention. Percentage of Civilian, Noninstitutionalized Population with Diagnosed Diabetes, by Age, United States, 1980-2010. Available at http://www.cdc.gov/diabetes/ statistics/prev/national/figbyage.htm. Accessed October 15, 2012. 4. Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012;28:8-14. 5. Hix M. Management of Diabetic Peripheral Neuropathic Pain. In Richardson M, Chant C, Cheng JWM, Chessman KH, Hume AL, Hutchinson LC, et al., eds. Pharmacotherapy Self-Assessment Program, 6th ed. Chronic Illnesses I. Lenexa, KS: American College of Clinical Pharmacy, 2009:21-38. 6. Nucynta ER (tapentadol-extended-release tablets) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; August 2012. Available at http:// www.nucynta.com/sites/default/files/pdf/nucyntaer-pi.pdf#zoom=100. Accessed November 1, 2012. 7. Vadivelu N, Timchenko A, Huang Y et al. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 2011;4:211-8. 8. Hoy SM. Tapentadol extended release in adults with chronic pain. Drugs 2012;72:375-93. 9. Schwartz S, Etropolski M, Shaprio DY et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin 2011;27:151-62.
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neuropathy, Geriatric, Nucynta ER, Tapentadol ER Abbreviations: DM = Diabetes mellitus, DPN = Diabetic
peripheral neuropathy, ER = Extended release, MOR-NRI = mu-opiod receptor agonist-norepinephrine reuptake inhibitor, NRS = Numerical rating scale, SAE = Serious adverse event, SNRI = Serotonin-norepinephrine reuptake inhibitor, SSRI = Selective-serotonin reuptake inhibitor, TCA = Tricyclic antidepressant, TEAE = Treatment-emergent adverse event. Consult Pharm 2013;28:672-5.
672
Background With more patients being diagnosed with diabetes mellitus (DM), pathological complications of DM are becoming more common. These complications include diabetic peripheral neuropathy (DPN).1-3 DPN has become the most common neuropathic syndrome seen in patients with DM, affecting up to 50% of patients.1 The estimated global prevalence of DM by 2030 will be 472 million individuals, suggesting that as many as 236 million patients may be affected by DPN.4 While the progression of DPN may be controlled with proper management of risk factors and glycemic control, the nociceptive and neuropathic pain associated with DPN is often chronic and difficult to manage.1-2,4 Approximately 10% to 20% of diabetic patients report painful DPN, resulting in increased morbidity, mortality, and substantial health care costs.1,4 Painful DPN is characterized as a burning, tingling, or aching sensation commonly affecting the lower limbs and typically worsening at night.2,4 The etiological cause of painful DPN is multifactorial, involving both central and peripheral mechanisms.4 Because of the complexity of the disease, medications with varying mechanisms of action may be needed to combat the refractory pain associated with DPN and to decrease the toxicity associated with its treatments.2 Current medications prescribed for painful DPN include tricyclic antidepressants (TCAs), anticonvulsants, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), opiates and opiatelike medications, and topical analgesics.2,5 While many medications can be recommended, until recently only pregabalin and duloxetine have received Food and Drug Administration (FDA) approval for DPN.2,5 Now, tapentadol ER [extended release] (Nucynta ER), a schedule II opioid analgesic commonly used for moderateto-severe chronic pain, has received FDA approval as the first and only opioid approved for symptomatic treatment of DPN, giving health care professionals an additional therapeutic choice.6
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Tapentadol-ER for the Treatment of Diabetic Peripheral Neuropathy
Pharmacology Profile While the exact mechanism of action is not clearly understood, preclinical trials of tapentadol ER demonstrate the analgesic effects resulting from the dual mechanism of μ-opioid receptor agonistic and norepinephrine reuptake-inhibitor activity (MOR-NRI).7-9 This distinct dual mechanism of action is suggested to represent a new pharmacological class: MOR-NRI.8 Tapentadol ER is considered a weak μ-opioid receptor-agonist, having an 18-fold decrease in receptor affinity compared with morphine.8 Despite the decrease in affinity, tapentadol ER only produced a two- to three-fold decrease in analgesic effects in animal studies.8 The analgesic effect can be explained by the synergistic interaction of the dual mechanism. The norepinephrine reuptake inhibition works by acting on the α-2 receptor located on the noxious nerve fibers in the spinal cord and central nervous system, inhibiting the transmission of pain impulses.7 The dual mechanism of tapentadol allows for potent analgesic effects that combat the complex pathology of neuropathic pain. Tapentadol ER preparation was developed to provide sufficient pain relief with the convenience of twice-daily dosing. It is available in 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets.6 The starting dose of tapentadol ER for opioid-naive patients is 50 mg twice daily, titrated to an effective and tolerable dose of 100 mg to 250 mg twice daily, with a maximum dose of 250 mg twice daily.8 The oral bioavailability of tapentadol ER is 32%, a result of extensive first-pass metabolism.6-8 The maximum serum concentration of tapentadol ER is increased by 17% when taken with a high-fat, high-calorie breakfast, but may be administrated without regard to meals.6,8 Peak serum concentrations occur three to six hours after administration, with steady-state concentrations achieved after the third dose.6 The parent tapentadol-ER drug is the active formulation, with 97% of the molecule metabolized by O-glucuronidation, resulting in its inactivation.6-8 The extensive hepatic metabolism of tapentadol ER accounts for the dose adjustments in hepatic impairment, extending the duration of administration to every 24 hours, with moderate hepatic impairment (Child-Pugh Score 7 to 9). It is subsequently contraindicated in severe hepatic
impairment.6 Tapentadol ER and its metabolites are excreted (99%) by the kidneys; regardless, no dose adjustments are required for renal impairment.6 Additional counseling points are located in Table 1.
Therapeutic Efficacy, Safety, and Tolerability The efficacy and safety of tapentadol ER for painful DPN has been evaluated by two DPN studies. Both studies included patients 18 years of age and older with either type 1 or type 2 DM and painful DPN for at least six months, with a pain-intensity score of at least 5 on an 11-point numerical rating scale (NRS). The studies consisted of two phases: a three-week, open-label phase during which all patients were titrated to an effective and tolerable tapentadol ER dose; and a 12-week, double-blind maintenance phase during which patients were randomized to either continue with their current tapentadol ER regimen or begin matching placebo. The primary endpoint analyzed was the change in average pain intensity.6,9 The first study was a randomized-withdrawal, placebo-controlled trial. A total of 591 patients entered into the open-label phase. Subsequently, 389 patients who achieved at least a one-point reduction in the NRS were randomized (1:1) for the maintenance phase. The age of the randomized study participants ranged from 29 to 87 (mean = 60 years).9 The second study was a doubleblind, parallel-group, randomized, placebo-controlled withdrawal trial. A total of 459 patients entered into the open-label phase, and 320 patients were randomized (1:1) for the maintenance phase. The age of the randomized study participants ranged from 28 to 83 years (mean = 59 years).9 Both studies reported that approximately twothirds of participants were opioid-naive.8,9 Both studies concluded tapentadol ER provided a statistically significant improvement of pain intensity compared with the placebo. During the open-label period, 60.5% of patients reported at least a 30% reduction in pain intensity, with 34.9% of patients reporting at least a 50% reduction in pain intensity. For the maintenance phase, 53.6% of patients randomized to the tapentadol ER treatment reported at least a 30% improvement by the end of
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Student Forum
Table 1. Counseling Points for Use with Tapentadol ER • Tapentadol ER must be dispensed with an FDA-approved medication guide. • Abuse Potential: Tapentadol ER is a schedule II controlled substance that is subject to abuse. • Life-threatening Respiratory Depression: Discuss risk with patients, explaining that the risk is greatest when first starting tapentadol ER or with an increase in dose. Special precaution should be taken with elderly patients because of an increased risk of respiratory depression. • Risks from Concomitant Use of Alcohol and other CNS Depressants: Inform patients about potentially serious additive effects (i.e., respiratory depression) if tapentadol is used with other CNS depressants. • Hypotension: Tapentadol ER may cause syncope and orthostatic hypotension. Patients should be advised to carefully rise from a sitting or lying position. • Seizures: Tapentadol ER could cause seizures if patients are at an increased risk for seizures or have epilepsy. • Important Administration Instructions: Tapentadol ER should not be cut, crushed, chewed, or dissolved. Source: Reference 6. Abbreviations: CNS = Central nervous system, ER = Extended release, FDA = Food and Drug Administration.
the 12-week maintenance phase. The least squares mean difference for the average change in pain-intensity score was statistically significant at 1.3 (95% confidence interval -1.70 to -0.92; P < 0.001).8,9 The incidence of treatment-emergent adverse events (TEAE) was 70.9% in the tapentadol ER study arm and 51.8% in the placebo study arm, with the most common side effects including nausea, anxiety, diarrhea, and dizziness. Most TEAEs reported were mild-to-moderate in intensity. Participant discontinuation was 20.1% in the open-label period, and 11.2% and 5.7% during the 12-week double-blind period for tapentadol ER and placebo, respectively. The most common TEAEs resulting in discontinuation included gastrointestinal (GI) adverse effects.9 Tapentadol ER has demonstrated an improved GI tolerability, compared with similar extended-release opioids.8 This increased tolerability is likely explained by the decreased affinity for the μ-opioid receptor.6-9 The incidence of treatment-emergent serious adverse
674
events (SAEs) was 5.1% in the tapentadol ER study arm and 1.6% in the placebo study arm. Most SAEs were determined to be unrelated to tapentadol ER.9
Conclusion With the rising incidence of DM and its associated complication of DPN, the utilization of medication to combat the chronic nociceptive pain will become more common.1-3 The FDA approval of tapentadol ER for the symptomatic treatment of painful DPN provides an additional therapeutic option with a unique mechanism of action.6 Tapentadol ER has proven safe and effective for the symptomatic treatment of DPN. As a result of the dual mechanism, studies suggest tapentadol ER may be particularly useful for complex pain encompassing both nociceptive and neuropathic pain components such as in DPN.6,9
The Consultant Pharmacist october 2013 Vol. 28, No. 10
Tapentadol-ER for the Treatment of Diabetic Peripheral Neuropathy
The Consultant Pharmacist publishes a Student Forum column to encourage student pharmacists to publish articles on geriatric pharmacotherapy. It is an opportunity for them to discuss recently published research or regulatory findings on medications, brief reviews of newly approved medications with potential use in elderly patients, or new uses or findings regarding approved medications relevant to the elderly population. Submissions may represent research, opinion, or analysis. Manuscripts submitted for this section have at least one pharmacy student author and must be coauthored by a pharmacy school faculty mentor. H. Edward Davidson, PharmD, MPH Editor-in-Chief [email protected]
Gina Games is a 2013 PharmD candidate, Auburn University Harrison School of Pharmacy, Auburn, Alabama. Amber Hutchison, PharmD, BCPS, is assistant clinical professor, Auburn University Harrison School of Pharmacy, Auburn, Alabama. For correspondence: Amber Hutchison, PharmD, BCPS, Auburn University Harrison School of Pharmacy, 1321 Walker Building (4201F), Auburn, AL 36849; Phone: 334-844-8401; Fax: 334-8444410; E-mail: [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2013 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2013.672
References 1. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes 2005;23:9-15. 2. Lindsay TJ, Rodgers BC, Savath V et al. Treating diabetic peripheral neuropathic pain. Am Fam Physician 2010;82:151-8. 3. Centers for Disease Control and Prevention. Percentage of Civilian, Noninstitutionalized Population with Diagnosed Diabetes, by Age, United States, 1980-2010. Available at http://www.cdc.gov/diabetes/ statistics/prev/national/figbyage.htm. Accessed October 15, 2012. 4. Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012;28:8-14. 5. Hix M. Management of Diabetic Peripheral Neuropathic Pain. In Richardson M, Chant C, Cheng JWM, Chessman KH, Hume AL, Hutchinson LC, et al., eds. Pharmacotherapy Self-Assessment Program, 6th ed. Chronic Illnesses I. Lenexa, KS: American College of Clinical Pharmacy, 2009:21-38. 6. Nucynta ER (tapentadol-extended-release tablets) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; August 2012. Available at http:// www.nucynta.com/sites/default/files/pdf/nucyntaer-pi.pdf#zoom=100. Accessed November 1, 2012. 7. Vadivelu N, Timchenko A, Huang Y et al. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res 2011;4:211-8. 8. Hoy SM. Tapentadol extended release in adults with chronic pain. Drugs 2012;72:375-93. 9. Schwartz S, Etropolski M, Shaprio DY et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin 2011;27:151-62.
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