Neuropharmacology & Neurotherapeutics
Gene therapy of cerebrovascular disease
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Tapentadol is a novel analgesic with combined opioid and adrenergic activity that was developed to fulfill some of the unmet needs in the management of acute pain and reduce the adverse effects of opioids. It may provide effective analgesic therapy for acute pain with both nociceptive and neuropathic components. Tapentadol immediate release (Tapentadol IR) was approved by the FDA in 2009 for the treatment of moderate to severe acute pain. It is the first new drug in the centrally acting analgesic class approved in the United States in more than 25 years. Tapentadol is listed in schedule II under the Controlled Substance Act (10). Rates of tapentadol immediate release (IR) abuse and diversion have been low during the first 2 years after its launch (09).
The full chemical name of tapentadol HCl is (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride.
Pharmacodynamics. Tapentadol is a centrally acting oral analgesic with a dual mechanism of action, combining mu-opioid receptor agonist and norepinephrine reuptake inhibition in a single molecule. Norepinephrine plays a role in the endogenous descending pain inhibitory system, and the analgesic efficacy of norepinephrine reuptake inhibitors has been shown in neuropathic pain. In a study on patients with diabetic polyneuropathy treated with sustained-release tapentadol, analgesic effect on chronic pain was demonstrated to be dependent on activation of descending inhibitory pain pathways as observed by conditioned pain modulation responses (17).
Analgesic effect of tapentadol has been demonstrated in a wide range of animal models of pain with nociceptive and neuropathic components, and development of tolerance to its analgesic effect was twice as slow as that of morphine. Although tapentadol has a 50-fold lower binding affinity to mu-opioid receptor, its analgesic potency is only 2 to 3 times lower than that of morphine, indicating that the dual mode of action may result in an opiate-sparing effect.
Pharmacokinetics. Important features of the absorption, metabolism, and excretion of tapentadol in humans using oral 3-[14C]-labeled tapentadol hydrochloride are:
• Drug absorption is rapid, reaching a maximum concentration of 2.45 microg-eq/mL in 1.25 to 1.5 hours.
• The drug is present mainly in the form of conjugated metabolites.
• Excretion is renal and complete within 5 days.
The absolute oral bioavailability of tapentadol is approximately 32%, which is comparable to that of morphine.
Various clinical trials of tapentadol during the past decade are summarized in Table 1.
Trial design and method
Randomized study of oral, twice-daily doses of tapentadol extended release or oxycodone controlled release for up to 1 year in patients with moderate to severe chronic knee or hip osteoarthritis or low back pain.
Tapentadol extended release was associated with better gastrointestinal tolerability than oxycodone and provided sustainable relief of pain over the study period (23).
A phase 3, multicenter, double-blind, randomized study of tapentadol IR on Korean adults with moderate-to-severe pain following foot surgery.
Tapentadol IR reduced acute pain intensity, significantly more than placebo (16).
A retrospective, single-center, open-label study in Japan on patients with advanced cancer who were resistant to opioids, such as tramadol, oral oxycodone, and transdermal fentanyl for relief of pain.
Tapentadol was effective in relieving cancer-related neuropathic pain that was refractory to first-line opioid treatment and produced less adverse effects than opioids (22).
Gastrointestinal tolerability demonstrated in clinical trials is expected to improve patient compliance and satisfaction. Tapentadol immediate release may offer a better option compared with other currently available analgesics for the relief of moderate to severe acute pain. Tapentadol immediate release has reduced opioid-related gastrointestinal adverse events while maintaining adequate analgesia, but further studies are required to establish its clinical usefulness in relation to that of tramadol and opioids other than oxycodone (12). Tapentadol immediate release has been evaluated in clinical trials in patients with postoperative pain after bunionectomy, and results show that it has better gastrointestinal tolerability than oxycodone immediate release at doses that provide comparable analgesia (08).
In well-designed short-term (15 week) clinical studies in adult patients with moderate to severe chronic pain associated with knee osteoarthritis, low back pain, or diabetic neuropathy, extended-release tapentadol 100 to 250 mg twice daily provided more effective pain relief and significantly improved functional outcomes compared with placebo (14). In longer-term studies (> 24 months) analgesic efficacy was maintained without development of tolerance. Results of an observational study have shown the long-term effectiveness, safety, and tolerability of oral prolonged-release tapentadol for the treatment of refractory chronic low back pain in a real-life clinical setting (11).
A systematic review of clinical trials of chronic pain requiring strong step 3 opioids of the WHO pain ladder and comparison to tapentadol showed a better benefit-risk ratio of tapentadol (18).
A summary of several phase 3 studies has shown that use of tapentadol extended release in patients with moderate to severe chronic pain was associated with better gastrointestinal tolerability and compliance with therapy than controlled release oxycodone (01). According to an analysis of prospective data from use in clinical practice, tapentadol prolonged release is effective and can be considered an alternative to strong opioids in the long-term management of chronic pain (21). A retrospective study has found that tapentadol is effective and well tolerated in opioid-naïve and opioid-tolerant patients with cancer pain of varying pathophysiology, including those with nociceptive and/or neuropathic components, and it may be considered for first-line use in moderate-to-severe pain (19).
Results of an observational retrospective study to comparatively assess the efficacy and tolerability of tapentadol in young and elderly patients with severe chronic low back pain show that tapentadol extended release maintains efficacy and good tolerability in these patients with advancing age (13).
Tapentadol is indicated for the management of moderate to severe acute pain. Extended-release tapentadol has been (Games and Hutchison 2013).
Tapentadol is contraindicated in following situations:
• Patients with significant respiratory depression, acute or severe bronchial asthma, or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.
• Patients who have or are suspected to have paralytic ileus.
• Patients currently using, or within 14 days of using, monoamine oxidase inhibitors due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.
The aim is control of acute pain and the dose can be titrated for optimal efficacy. In clinical trials tapentadol has been used safely for 90 days. In an open-label extension study, pain relief obtained during the preceding studies was maintained throughout this extension study, during which tapentadol extended-release was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment (04). Aim of relief of acute pain with tapentadol is to prevent development into chronic pain through neuroplasticity with modification of pain pathways, and availability of different doses helps tailor treatment for individual patients to provide adequate relief (07). Tapentadol has a unique analgesic profile, which is different from classical opioids; therefore, it may be a good choice for the treatment of chronic, neuropathic, and mixed pain with less adverse effects than opioids (05).
One tapentadol tablet of 50 mg, 75 mg, or 100 mg can be taken orally every 4 to 6 hours depending on pain intensity. Patients can receive a second dose 1 hour after initial dose, if needed on day 1. Maximum 24-hour dose of tapentadol on day 1 is 700 mg and on subsequent days is 600 mg. Higher doses have not been studied and are, therefore, not recommended. It is available in the immediate release form for acute pain and as an extended-release formulation for chronic pain when continuous analgesia is required.
Tapentadol is not recommended in patients with severe renal or hepatic impairment and should be used with caution in patients with moderate impairment of function of these organs. Tapentadol should be prescribed with care in patients with a history of a seizure disorder. The effect of tapentadol on seizures is unknown as such patients were excluded in clinical trials. Withdrawal symptoms may occur if the drug is discontinued abruptly after use for a prolonged period.
Anesthesia. Patients on tapentadol may exhibit additional CNS depression during general anesthesia.
Pediatric. Most the patients in a retrospective observational study that examined the toxic effects of a single dose of tapentadol in the age group 0 to 17 had no adverse effect from the exposure, and only 2 had life-threatening events (03). The most common adverse effects reported were like those that occur with the use of opioids.
Geriatric. Tapentadol should be administered with caution to elderly, debilitated patients who are more likely to suffer respiratory depression. A pooled analysis of randomized clinical trials shows that elderly patients (75 years of age or older) with moderate to severe low back pain obtained significant pain relief from extended-release tapentadol (100 to 250 mg twice daily) compared with placebo, with a better overall gastrointestinal tolerability than controlled release oxycodone (02).
Pregnancy. There are no adequate and well-controlled studies of tapentadol use in pregnant women. Tapentadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking tapentadol should be monitored for respiratory depression. Tapentadol should not be used during breast feeding.
Because of low protein binding capacity, absence of active metabolites, and significant microsomal enzyme induction or inhibition, potential for drug-drug interactions of tapentadol is limited (24). Tapentadol was evaluated for induction and inhibition of several cytochrome P450 enzymes in vitro; it was concluded that no clinically relevant drug-drug interactions are likely to occur through this mechanism (15). There are no clinically relevant interactions when tapentadol is given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid, and no dosage adjustments are required (20).
The most common adverse events are nausea, dizziness, vomiting, somnolence, and headache. Opioid-related gastrointestinal adverse effects are significantly reduced as compared with pure opioid agonists because of the lower dosage required for efficacy in pain relief. Serious and life-threatening adverse effects are rare and may include respiratory depression, electrolyte abnormality, seizures, coma, hypertension, or atrial fibrillation (06).
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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