Tapentadol A Promising Option For Neuropathic Pain

Today's post from diabetesincontrol.com (see link below) talks about Tapentadol (Nucynta) being effective for diabetes-related neuropathy pain. Earlier articles on this blog (see alphabetical list to the right) have highlighted its efficacy for HIV-related neuropathy and other neuropathies also fall under its benefits (but as yet not approved for all). So why isn't this breakthrough semi-opiate ending up as a front-line treatment? The answer seems to lie in the cost and the competition between drug companies, which disregards the needs of the patients, who have been looking for an efficient chronic pain management drug with less side effects than its competitors. The FDA has approved it, which is the first major step with any new drug but doctors throughout the western world are possibly being pressured into not prescribing it due to pressure from health insurance companies who are always looking for cheaper options. It's symptomatic of a culture where economic cuts are paramount and the power of established drug company lobbies has never been stronger. However, if Tapentadol really is a better option for many patients living with neuropathy, then denying them access is at the very least, morally questionable.

Tapentadol-ER for the Treatment of Diabetes Associated Peripheral Neuropathy (DPN)  This article originally posted 26 June, 2014 and appeared in Medication, Neuropathy, Pain, Issue 735

The FDA recently approved tapentadol-ER (Nucynta ER) for the treatment of peripheral neuropathy in diabetics....

Advertisement With an increasing number of patients being diagnosed with diabetes, complications associated with the disease are becoming more common.  Diabetic peripheral neuropathy (DPN) is the most common neuropathic pain seen in patients with diabetes, affecting up to 50% of patients. It is characterized as a burning or tingling sensation that affects the lower limbs. Painful DPN is associated with increased morbidity, mortality and substantial costs to the healthcare system. Tapentadol-ER is a schedule II opioid analgesic that is commonly used for the treatment of moderate to severe chronic pain. It is unique in its dual acting mechanism in which it works as both a weak mu-opioid receptor agonist and a norepinephrine-reuptake inhibitor. This distinct mechanism is said to represent a new pharmacological class of medications: MOR-NRI. Tapentadol ER is a weak mu-opioid receptor agonist, having an 18 fold decrease in receptor affinity when compared to morphine. Despite this decrease in affinity, tapentadol ER only produces a two to three fold decrease in analgesic effects when studied in animals. It also acts on the alpha-2 receptor located on the noxious nerve fibers in the spinal cord and throughout the central nervous system, inhibiting transmission of pain impulses. The dual acting mechanism of tapentadol-ER works to control the complex pathology that is neuropathic pain. Until this approval the only options for FDA approved medications to treat diabetic peripheral neuropathy (DPN) were pregabalin and duloxetine. Tapentadol ER provides sufficient pain relief with convenient twice daily dosing. The starting dose for opioid-naïve patients is 50mg twice daily and can be titrated to an effective dose of 100mg to 250mg twice daily. The maximum daily dose is 250mg twice daily. The maximum serum concentration is increased by 17% when taken in combination with a high fat breakfast but according to package labeling may be administered without regards to food. Tapentadol-ER undergoes extensive hepatic metabolism and therefore must be adjusted in patients with hepatic impairment. The usual adjustment is extension of administration duration to once every 24 hours in patients with mild to moderate hepatic impairment (Child-Pugh Score of 7 to 9). It is contraindicated in patients with severe hepatic impairment. Tapentadol ER and its metabolites are excreted by the kidneys; however, no dose adjustments are required for patients with renal impairment. The efficacy and safety of tapentadol ER has been studied in two DPN studies. Both studies were placebo controlled randomized studies in which patients had either type 1 or type 2 diabetes and painful DPN for a period of at least six months. Pain intensity was at least a 5 on an 11 point scale. In both studies approximately two-thirds of participants were opioid-naïve. Both studies came to the conclusion that tapentadol ER provided statistically significant improvement of pain intensity as compared to that of placebo. Treatment related adverse effects were reported at 70.9% for those taking tapentadol ER and 51.8% for those taking placebo. The most common side effects were nausea, diarrhea, anxiety and dizziness. Most were mild to moderate and did not lead to discontinuation of the medication. Practice Pearls: The incidence of diabetes is on the rise as is the complication of neuropathy The FDA approval of tapentadol ER for treatment of diabetic peripheral neuropathy provides practitioners an additional therapeutic option with a convenient twice daily dosing regimen. Tapentadol ER has a unique dual mechanism suggesting that it may be particularly useful for complex pain associated with DPN. Consult Pharm. 2013 Oct;28(10):672-5. doi: 10.4140/TCP.n.2013.672 Comment from Dr. Aaron Vinik, Diabetes In Control Advisory Board member, and study author: Pain associated with DPN is a common complication of diabetes affecting 10-26% of patients for which the only approved drugs are Pregabalin and Duloxetine which at best reduce pain by 30% in about half the patients treated leaving a significant portion of the affected population without resort to significant pain relief. A paradox here is that third party payors insist that less expensive drugs such as the tricyclics should be used as first line despite the fact that they have cardiovascular cautions as well as not paying heed to the need for attention to the comorbidities of sleep loss, depression and anxiety as determinants of choice of initial therapies. However, the problem occurs when first line therapies have failed and the need for greater reduction of pain arises wherein a combination of drugs acting through different parts of the pain pathway have proved useful. The problem with this approach is that this increases the burden of drugs patients with diabetes must take with untoward effects, particularly cognitive impairment, which can have a disastrous impact on decision-making and is the cause of induced hypoglycemia and its consequences. Tapendalol represents a proposed new class of centrally acting analgesics combining two mechanisms of action: u-opiod receptor agonism and norepinephrine reuptake inhibition. Tapentadol extended release has been shown to be effective and well-tolerated for the management of severe, chronic pain in randomized, double blind, placebo-controlled and/or active comparator controlled phase 3 studies. Two studies (of which I am first author and coauthor of the second) were designed using a randomized withdrawal multicenter placebo control design and reached their primary endpoint and in August 2012 tapentadol ER received FDA approval for the mangement of pain associated with DPN in adults when a continuous around the clock opiod analgesic was needed for an extended period of time. To determine if subgroups would benefit, the data from the two studies were pooled. The results of this pooled analysis indicated that tapentadol ER is effective and well-tolerated for the management of neuropathic pain associated with DPN, improved measures of health related quality of life and had constent efficacy across different patient subgroups divided by age, gender, race, opiod experience and pain intensity. Sensitivity analyses showed that in the tepentadol arm ( n=360) compared with placebo ( n=342) the drug 54% achieved >30% pain reduction and 38.9%;50% pain reduction and the significant side effects were nausea, vomiting, dizziness, and somnolence. These figures argue in favor of using the drug as a second or third tier drug with the recognition that its effects are modest and there is the potential for habituation. Ultimately, what is needed is a drug that will reverse the pathogenic process and that the need for pain-relieving drugs will be the bandaid to be used in the interval before the damage to the nervous system has been resolved.  http://www.diabetesincontrol.com/articles/diabetes-news/16529-tapentadol-er-for-the-treatment-of-diabetes-associated-peripheral-neuropathy-dpn

Tapentadol A New Alternative For Neuropathic Pain

Today's post comes from marketwatch.com (see link below) and is a press release for Tapentadol, a new centrally-acting opioid made by Janssen Pharmceuticals to control neuropathic pain. Far be it from me to promote either a company or an opioid but we're always looking for alternatives to the treatments that either don't work, or have unpleasant side effects. This is another opium derivative, so there will undoubtedly be issues regarding side effects and addiction for some people but the tests look promising. The post is long because Janssen have provided a complete description of how the drug works and what the potential side effects may be and that's worth reading. One assumes that this information will all appear on the leaflet inside the box when the drug achieves general release. Tapentadol will not be for everybody, as is the case for all similar treatments but it may be a breakthrough for some. Time will tell.
More information about Tapentadol can be found here (and is easier to digest),

Phase 3 Data Show NUCYNTA® ER (tapentadol) Extended-Release Tablets Provide Pain Management for Patients with Diabetic Peripheral Neuropathy (DPN)

Study results presented at the 31st Annual Scientific Meeting of the American Pain Society

press release May 17, 2012,

RARITAN, N.J., May 17, 2012 /PRNewswire via COMTEX/ -- Janssen Pharmaceuticals, Inc. today announced the results of an investigational Phase 3 study suggesting NUCYNTA® ER (tapentadol) extended-release tablets were significantly more effective than placebo in providing pain management among adults with chronic moderate to severe, painful diabetic peripheral neuropathy (DPN). Results of the study were presented at the 31st Annual Scientific Meeting of the American Pain Society being held May 16-19 in Honolulu, Hawaii.

Diabetes affects nearly 26 million people in the United States(1)- and its prevalence is expected to grow significantly during the coming decades(2). Over time, people with diabetes can develop a type of nerve damage called neuropathy. Approximately 60 to 70 percent of people with diabetes have some form of neuropathy(3). The most common type is diabetic peripheral neuropathy, which causes pain or loss of feeling in the toes, feet, legs, hands, and arms.

The study found, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with tapentadol ER, those who continued on an optimized dose of tapentadol ER (100-250 mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo(4). Treatment-emergent adverse events reported in 10 percent or more of tapentadol ER-treated patients during the double-blind maintenance period included nausea (21.1 percent) and vomiting (12.7 percent)(4).

"Painful DPN is a common and burdensome complication of diabetes, and controlling pain in people with DPN can be challenging," said Aaron I. Vinik, M.D., Ph.D., FCP, MACP, Director of Research and Neuroendocrine Unit at Strelitz Diabetes Center for Endocrine and Metabolic Disorders at Eastern Virginia Medical School, and lead investigator of the study. "These data suggest tapentadol ER provides a significant reduction in chronic pain in adult patients with DPN."

The findings of this study are consistent with those of another Janssen-sponsored study published early last year, which found tapentadol ER to be effective versus placebo for relieving moderate to severe chronic pain associated with diabetic peripheral neuropathy.

"We are pleased the Phase 3 data presented today showed tapentadol ER was effective at providing pain management for patients with chronic, moderate to severe pain associated with DPN," said Christine Rauschkolb, M.D., Ph.D., Vice President and Head of Integrated Operations, Janssen Research & Development, LLC and one of the study's authors. "Janssen has a long history of helping physicians provide responsible treatment for patients to relieve their acute and chronic pain. We are committed to developing new pain management options for the millions of Americans who have painful DPN."

About the Study

This Phase 3 clinical trial was a randomized-withdrawal, placebo-controlled study. It enrolled adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. This trial had three phases: an open-label phase, which included a 3-week titration period during which the individually optimized tapentadol ER dose (100-250 mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking tapentadol ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10 to 14 days after discontinuation of study drug.

The primary efficacy endpoint of the study was the mean change in average pain intensity from baseline (point of randomization) to the last week of the 12-week, double-blind maintenance phase, as determined by an 11-point pain rating scale or numerical rating scale (NRS; 0='no pain,' 10='pain as bad as you can imagine'). Safety assessments were performed on the open-label and double-blind safety populations (all patients who received greater than or equal to 1 dose of open-label and double-blind treatment, respectively). Treatment-emergent adverse events (TEAEs), defined as any AEs (new or worse in intensity) that occurred after the first intake of study drug during the open-label or double-blind phase, were monitored throughout the study.

In the open-label titration period, 459 patients received one or more doses of tapentadol ER and were included in the open-label safety population. At the start of the 3-week, open-label phase, the majority of patients (87.1 percent) reported severe pain (6 or more on the 11-point NRS) with a mean pain intensity of 7.3. By the end of the open-label phase, the mean pain intensity was reduced to 3.6. Treatment-emergent adverse events (TEAEs) experienced by 10 percent or more of patients during the open-label phase were nausea (24.4 percent), dizziness (17), constipation (11.8) and somnolence (10.7).

A total of 358 patients completed the open-label titration period; 318 were randomized and received one or more dose of study medication (n=152 for placebo, 166 for tapentadol ER).

Following randomization, during the double-blind treatment phase to week 12, pain increased in the placebo group (as demonstrated by the mean change in pain intensity of 1.3), while in the tapentadol ER group, efficacy was maintained, as indicated by the mean change in pain intensity of 0.28. The least-squares mean difference between the tapentadol ER and placebo groups in the change in average pain intensity was -0.95 on the 11-point NRS favoring tapentadol ER (95 percent CI, -1.42 to -0.49; p<0.001, tapentadol ER vs. placebo)(4).

For more details about the study design, please visit www.clinicaltrials.gov (NCT01041859).

Janssen Research & Development, LLC and Grunenthal GmbH, conducted this study, which Janssen Research & Development, LLC has included as part of its Supplemental New Drug Application (sNDA) submitted on October 28, 2011 to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of neuropathic pain associated with DPN in patients 18 years of age or older. The FDA currently is reviewing this supplemental application.

About Tapentadol and NUCYNTA® ER

Tapentadol is a centrally-acting synthetic analgesic. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA® ER (tapentadol) extended-release tablets are an oral analgesic available by prescription only and indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. NUCYNTA® ER is taken twice daily and available in 50 mg, 100 mg, 150 mg, 200 mg and 250 mg strengths.

Outside the United States, tapentadol is marketed by Janssen Inc. in Canada; Grünenthal GmbH discovered tapentadol and markets immediate- and extended-release formulations of tapentadol (PALEXIA®) in various countries in Europe.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA® ER (tapentadol) extended-release tablets

WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTION, AND LIMITATIONS OF USE

Potential for Abuse

NUCYNTA® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances, which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection

NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use

NUCYNTA® ER is not intended for use as an as-needed analgesic.

NUCYNTA® ER is not intended for the management of acute or postoperative pain.

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.

Patients must not consume alcoholic beverages, or prescription or nonprescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA® ER may result in a potentially fatal overdose of tapentadol.

CONTRADICTIONS

NUCYNTA® ER 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® ER is contraindicated in any patient who has or is suspected of having a paralytic ileus.

NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

NUCYNTA® ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.

WARNINGS & PRECAUTIONS

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, crushed, or dissolved NUCYNTA® ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.

NUCYNTA® ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTA® ER, especially in children, can result in a fatal overdose of tapentadol.

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.

Use NUCYNTA® ER with caution in 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, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA® ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered, and NUCYNTA® ER 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 opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® ER 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® ER. 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® ER should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure, such as those with evidence of 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® ER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

Tapentadol 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.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carries the risk of addiction even under appropriate medical use.

Drug abusers may attempt to abuse NUCYNTA® ER by crushing, chewing, snorting, or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA® ER and pose a significant risk to the abuser that could result in overdose and death.

NUCYNTA® ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (eg, phenothiazines, general anesthetics).

Patients should be cautioned that NUCYNTA® ER 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® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma, or death may result.

NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA® ER 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.

Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.

Withdrawal symptoms may occur if NUCYNTA® ER 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® ER.

A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.

NUCYNTA® ER has not been studied in patients with severe hepatic impairment, and use in this population is not recommended.

Like other drugs with mu-opioid agonist activity, NUCYNTA® ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

NUCYNTA® ER should be used with caution in the following conditions: adrenocortical insufficiency (eg, Addison's disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis.

Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA® ER in pregnant women. NUCYNTA® ER should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus.

ADVERSE REACTIONS

The most common (greater than equal to 10%) adverse reactions were nausea, constipation, headache, dizziness, and somnolence.

About Janssen Pharmaceuticals, Inc. and Janssen Research and Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop and bring innovative products, services and solutions to people throughout the world.

Janssen Pharmaceuticals, Inc., and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies.

Janssen Pharmaceuticals, Inc. provides medicines for an array of health concerns in several therapeutic areas. Innovative therapies Janssen Pharmaceuticals, Inc. offers currently include ACIPHEX® (rabeprazole sodium), DORIBAX® (doripenem for injection), ELMIRON® (pentosan polysulfate sodium), NUCYNTA® (tapentadol), NUCYNTA® ER (tapentadol) extended-release tablets and XARELTO® (rivaroxaban) tablets. The full prescribing information for NUCYNTA® ER, including boxed warnings, is available here; the full prescribing information for XARELTO®, including boxed warnings, is available here.

For more information on Janssen Pharmaceuticals, Inc., visit us at www.janssenpharmaceuticalsinc.com or follow us on Twitter at www.twitter.com/JanssenUS .

For more information on Janssen Research & Development, LLC, visit us at http://www.janssenrnd.com/ .

http://www.marketwatch.com/story/phase-3-data-show-nucynta-er-tapentadol-extended-release-tablets-provide-pain-management-for-patients-with-diabetic-peripheral-neuropathy-dpn-2012-05-17

Tapentadol An Opioid Option For Severe Neuropathy

Today's article from medscape .com (see link below) talks about a drug that has been on the market for a short time  but has had displayed good results for patients with severe and painful neuropathy. The problem is that it's an opioid (although one of the better-tolerated opioids) and there are two objections that stand in the way of it being more widely prescribed. It's apparently expensive and insurance companies are reluctant to pay for it and possibly because of that, the moral argument against opioids in general (addiction dangers, public image) is strengthened. Tapendatol (Nucynta) however, has had such good results with less side effects, that many specialists are wondering why it isn't more widely prescribed. You are unlikely to be prescribed opioids unless your pain is severe and chronic and you've already been through the gamut of other options and even then many doctors are also biased against opioids. New evidence has shown however, that if used properly and under supervision, opioids can be extremely useful in reducing nerve pain and improving the quality of life of patients and Tapentadol seems to be step forward in refining opioids for safer use. Maybe worth discussing with your doctor, if the pain is affecting your life badly.

Tapentadol is 'Third-Tier' Drug for Diabetic Neuropathic Pain
Lara C. Pullen, PhD June 04, 2014

The opioid analgesic tapentadol (Nucynta, Janssen Pharmaceuticals) is approved for use in patients with painful diabetic peripheral neuropathy in the United States, but it is expensive, and most insurance companies require physicians to first attempt multiple other drugs before prescribing it, says the lead author of a new paper describing the efficacy and tolerability of this agent.

The agent is also a scheduled narcotic, which further deters doctors; thus, tapentadol is currently a "third-tier" drug for the treatment of diabetic peripheral neuropathy, Aaron I. Vinik, MD, PhD, from East Virginia Medical School in Norfolk, told Medscape Medical News.

Dr. Vinik and colleagues' findings were published online May 21 in Diabetes Care. While the results show tapentadol is an effective treatment for diabetic peripheral neuropathy, "it is not being prescribed as much as I thought it would be," he said.

John D. England, MD, from the department of neurology at Louisiana State University Health Sciences Center School of Medicine in New Orleans, who was not involved with this research, agrees that doctors are uncomfortable prescribing this agent.

"[Tapentadol] is a [Drug Enforcement Administration] schedule II narcotic and has significant potential for abuse and addiction. It is only indicated for moderate to severe pain. For the treatment of neuropathic pain, there are many other drugs that are safer and have fewer adverse effects. This drug, like all opioids, would be a last-tier option for neuropathic pain," he explained in an email.

Dr. Vinik says he also has another reason to hesitate when considering tapentadol for this indication, "I prescribe it in very specific circumstances. I am keen on managing diabetic peripheral neuropathy based on comorbidity," he elaborated.

Tapentadol ER Effective and Well Tolerated

An extended-release (ER) formulation of tapentadol was approved for use in painful diabetic peripheral neuropathy by the Food and Drug Administration in August 2012, and the United States is currently the only country in which this agent is approved for this indication.

In the newly published study by Dr. Vinik and colleagues, adults with moderate to severe diabetic peripheral neuropathy pain were titrated to tapentadol ER 100 to 250 mg twice daily during a 3-week open-label period. Patients with 1-point or more reduction in pain intensity (11-point numerical rating scale) at the end of titration were then randomized to receive placebo or tapentadol ER, at the optimal dose determined from titration, for a 12-week, double-blind, fixed-dose maintenance phase.

The primary end point was mean change in average pain intensity from the start to week 12 of the double-blind maintenance phase.

A total of 358 patients completed the titration period; 318 patients (placebo, n=152; tapentadol ER, n=166) were randomized and received 1 or more doses of double-blind study medication. Mean pain intensity was 7.33 at the start and 4.16 at week 3 of the open-label titration period (mean change, –3.22).

The mean change in pain intensity (a positive value indicates worsening of pain) from start of double-blind treatment to week 12 was 1.30 for placebo vs 0.28 for tapentadol ER (P lt; .001 in favor of tapentadol).

Dr. Vinik said while there was quite a high rate (35%) of gastrointestinal disturbances, such as nausea and vomiting, observed with tapentadol ER, as well as a high rate of dizziness (12%) and headache (4%), the side effects did not stop patients from taking the medication.

"Tapentadol ER (100–250 mg [twice daily]) was effective and well tolerated for the management of moderate to severe chronic pain associated with diabetic peripheral neuropathy," he and his colleagues conclude.

Treating Pain Based on Comorbidity

However, in practice, Dr. Vinik noted that many patients with painful diabetic neuropathy also experience sleep disorders, anxiety, and/or depression. So physicians should ideally prescribe drugs that will treat as many of these comorbidities as possible, looking for the best fit with the total clinical picture of a patient.

If a pharmaceutical treatment can ameliorate sleep disturbance, it may also have a significant effect on pain, he noted. Unfortunately, in the case of tapentadol and many other drugs prescribed for diabetic neuropathy, their effect on sleep has not been well studied, he observed.

While many physicians and patients believe a number of commonly prescribed medications to have a beneficial effect on sleep, research shows that while an agent may make a patient tired, for example, it doesn't necessarily help the patient to sleep. For instance, a commonly prescribed drug for diabetic neuropathy, duloxetine (Cymbalta, Eli Lilly), actually fragments sleep, he explained.

Dr. Vinik suggests that, when treating a patient with diabetic peripheral neuropathy and sleep disturbance, a gabapentinoid may be the best option.

Anxiety is a common comorbidity with diabetic neuropathy, too, but unfortunately, tapentadol is also not particularly effective for anxiety, he added, noting that tricyclic antidepressants may be the best option for these 2 coexisting conditions.

He warns, however, that tricyclics may have cardiac effects, and thus physicians should take care to evaluate the cardiac status of patients before and after prescribing these older antidepressants.

Depression and Diabetic Neuropathy: A Good Fit for Tapentadol?

The other common comorbidity, occurring in approximately half of all patients with diabetic neuropathy is depression. While tricyclics may be an effective treatment for depression alone, they do not appear to ease the pain of patients with both conditions.

While he cautioned that patients who are bipolar do not respond well to either tapentadol or duloxetine, he said that the unique properties of tapentadol — it is a combination of a µ-opioid-receptor agonist and a norepinephrine-reuptake inhibitor in a single molecule — means it is possible for the physician to prescribe 1 drug instead of 2 for patients with diabetic peripheral neuropathy and classic depression.

For this reason, tapentadol is a good addition to the physician arsenal and can be extremely beneficial for the right patient because it not only relieves pain but also has the potential to elevate mood, he concluded.

Editorial support was funded by Janssen Research and; Development and Grünenthal. Dr. Vinik received funding for this study from Janssen; disclosures for the authors are listed in the article. Dr. English has reported no relevant financial relationships.

Diabetes Care. Published online May 21, 2014. Abstract

http://www.medscape.com/viewarticle/826174

Nucynta tapentadol For Neuropathy

Today's complex post from centerwatch.com (see link below) talks about Nucynta (tapentadol) which in simplistic terms, is both an opioid and non-opioid  compound, working in one tablet. To provide some sort of comparison point, it sits somewhere between Tramadol and morphine. Once again it is initially directed at diabetic neuropathy sufferers but because it's an analgesic aimed at reducing neuropathic pain, it surely will apply to most neuropathy pain symptoms, where the pain has become severe. Hopefully the promising results from this phase 3 trial will soon be translated into another option for people with neuropathic pain.

Janssen’s Nucynta meets primary endpoint in diabetic peripheral neuropathy study

Monday, May 21, 2012 02:46 PM

Janssen Pharmaceuticals has issued results from an investigational phase III study suggesting Nucynta ER (tapentadol) extended-release tablets were significantly more effective than placebo in providing pain management among adults with chronic moderate to severe, painful diabetic peripheral neuropathy (DPN).

The study found, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with tapentadol ER, those who continued on an optimized dose of tapentadol ER (100-250mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo. Treatment-emergent adverse events reported in 10% or more of tapentadol ER-treated patients during the double-blind maintenance period included nausea (21.1%) and vomiting (12.7%).

"Painful DPN is a common and burdensome complication of diabetes, and controlling pain in people with DPN can be challenging," said Aaron I. Vinik, M.D., Ph.D., FCP, MACP, lead investigator of the study. "These data suggest tapentadol ER provides a significant reduction in chronic pain in adult patients with DPN." The most common type is diabetic peripheral neuropathy, which occurs in 60-70% of diabetics and causes pain or loss of feeling in the toes, feet, legs, hands and arms.

This phase III clinical trial was a randomized-withdrawal, placebo-controlled study. It enrolled adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. This trial had three phases: an open-label phase, which included a 3-week titration period during which the individually optimized tapentadol ER dose (100-250 mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking tapentadol ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10 to 14 days after discontinuation of study drug.

The primary efficacy endpoint of the study was the mean change in average pain intensity from baseline (point of randomization) to the last week of the 12-week, double-blind maintenance phase, as determined by an 11-point pain rating scale or numerical rating scale (NRS; 0='no pain,' 10='pain as bad as you can imagine').

In the open-label titration period, 459 patients received one or more doses of tapentadol ER and were included in the open-label safety population. At the start of the 3-week, open-label phase, the majority of patients (87.1%) reported severe pain (6 or more on the 11-point NRS) with a mean pain intensity of 7.3. By the end of the open-label phase, the mean pain intensity was reduced to 3.6. Treatment-emergent adverse events (TEAEs) experienced by 10% or more of patients during the open-label phase were nausea (24.4%), dizziness (17%), constipation (11.8%) and somnolence (10.7%).
A total of 358 patients completed the open-label titration period; 318 were randomized and received one or more dose of study medication (n=152 for placebo, 166 for tapentadol ER).

Following randomization, during the double-blind treatment phase to week 12, pain increased in the placebo group with a mean change in pain intensity of 1.3, while in the tapentadol ER group, efficacy was maintained, with a mean change in pain intensity of 0.28. The least-squares mean difference between the tapentadol ER and placebo groups in the change in average pain intensity was -0.95 on the 11-point NRS favoring tapentadol ER (95% CI, -1.42 to -0.49; p<0.001, tapentadol ER vs. placebo).

http://www.centerwatch.com/news-online/article/3358/janssens-nucynta-meets-primary-endpoint-in-diabetic-peripheral-neuropathy-study