Opioid Agents Research Articles

Rapid onset opioids in palliative medicine.

Opioids are potent broad-spectrum analgesics useful to treat a variety of painful conditions. Opioids have been classified by many different categorizations (e.g. natural, semisynthetic, synthetic). One classification that may be useful in terms of selecting specific opioid agents is based on the pharmacokinetic characteristics of the various opioid formulations (e.g. longacting opioids, short-acting opioids, and rapid onset opioids). These various opioid agents appear to be useful to "match" specific types of pains. Rapid onset opioids appear especially well-suited to treat breakthrough pain and in particular, rapidonset breakthrough pain. This article will briefly review 5 rapid onset opioids that are FDA approved in the U.S.

Clinical Anesthesia and Analgesia in Fish

Fish have become a popular experimental model and companion animal, and are also farmed and caught for food. Thus, surgical and invasive procedures in this animal group are common, and this review will focus on the anesthesia and analgesia of fish. A variety of anesthetic agents are commonly applied to fish via immersion. Correct dosing can result in effective anesthesia for acute procedures as well as loss of consciousness for surgical interventions. Dose and anesthetic agent vary between species of fish and are further confounded by a variety of physiological parameters (e.g., body weight, physiological stress) as well as environmental conditions (e.g., water temperature). Combination anesthesia, where 2 anesthetic agents are used, has been effective for fish but is not routinely used because of a lack of experimental validation. Analgesia is a relatively underexplored issue in regards to fish medicine. However, recent studies have investigated opioid agents, nonsteroidal antiinflammatory drugs, and local anesthetics to determine their efficacy in minimizing pain and discomfort. The opioid morphine and the local anesthetic lidocaine do have significant effectiveness in reducing pain-related responses in rainbow trout (Oncorhynchus mykiss). Studies aimed at developing reliable analgesic protocols should explore a wide range of analgesic drug classes in several fish species.

The Metabolism of Opioid Agents and the Clinical Impact of Their Active Metabolites

The metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. This is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. An understanding of "opioid metabolic machinery," cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. A greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes.

Economic Impact of Potential CYP450 Pharmacokinetic Drug–Drug Interactions Among Chronic Low Back Pain Patients Taking Opioids

Chronic low back pain (cLBP) patients who take at least 1 CYP450-metabolized opioid analgesic agent concurrent with at least 1 other CYP450-metabolized medication experience a drug-drug exposure (DDE), which puts them at risk for a pharmacokinetic drug-drug interaction (PK DDI). This study compared utilization of healthcare resources and associated payments in cLBP patients with and without incident DDEs with the potential to cause PK DDIs. A retrospective database analysis examined the associated clinical events, healthcare utilization (measured in terms of claims for office visits, outpatient visits, emergency department visits, and hospitalization), and cost to the health plan, as defined as the sum of health plan payments for resources used. Patients were grouped into 2 cohorts by age (those under 65 and those 65 years and over). In the 6 months after exposure, total healthcare payments were significantly higher for DDE patients than those without DDEs (no-DDE), in both in the younger ($7,086, SD = $8,370) and $6,353, SD = $8,352, respectively, P < 0.001) and the older cohorts ($7,806 vs. $7,043, respectively, P = 0.013). Younger and older patients with DDE had significantly higher prescription payments than those without DDE ($2,041, SD = $2,706 vs. $1,565, SD = $2,349, respectively, P < 0.001 for younger and $2,482, SD = $2,481 vs. $2,286, SD = $2,521, respectively, P = 0.044 for older patients). Both older and younger patients with DDE had significantly more claims for office visits and higher associated payments than similar patients without DDE. Patients in the study who experienced DDEs that placed them at risk for PK DDIs had significantly greater utilization rates of healthcare resources and higher associated payments in the 6-month observation period following exposure.

Opioid-induced biochemical alterations of the neuroendocrine axis

Exogenous opioids have been used for decades to palliate cancer-related pain and other cancer-related manifestations and, more recently, to treat patients with pain not related to oncologic disease. While the goal of opioid treatment is symptomatic relief and improved quality of life, these patients often suffer from adverse side effects, including endocrine system abnormalities, of which hypogonadism is the best known. Opioids may interact with other hypothalamic–pituitary pathways and endocrine end organs, and in most cases these interactions are subtle and the effects unclear. The long-term effects of these agents on the endocrine system are still largely unknown. This article discusses the various effects of opioid agents on the endocrine system and provides information that allows early recognition of side effects that may alter the quality of life of patients affected by pain, awareness of the potential complications in opioid addicts, and detection and treatment of side effects in participants of an opioid detoxification program.

Human mu‐opioid receptor gene A118G polymorphism predicts the efficacy of tramadol/acetaminophen combination tablets (ultracet) in oxaliplatin‐induced painful neuropathy

The A118G polymorphism of the mu-opioid receptor gene (OPRM1), resulting in the substitution of an amino acid, has been found to be associated with functional effects and response to opioid treatment. The purpose of this study was to assess whether this polymorphism contributes to the variability in response to tramadol/acetaminophen combination tablets (Ultracet) for treating oxaliplatin-induced painful neuropathy. A total of 96 patients with adenocarcinoma of the colon or rectum (n = 84), or stomach (n = 12) who had developed oxaliplatin-induced painful neuropathy were enrolled. Ultracet was administered at 1 tablet every 6 hours, and pain was assessed and scored using a visual analog scale (VAS). The OPRM1 A118G polymorphism was examined with a polymerase chain reaction-direct sequencing method. The allelic frequency of variant (118G) allele was 39.6%, and the prevalence of OPRM1-118 AA, AG, and GG genotypes was 31.3% (n = 30), 58.3% (n = 56), and 10.4% (n = 10), respectively. For all patients, the mean pre-treatment and post-treatment VAS scores were 3.1 and 2.1, respectively (P < .001). Patients with AA genotype had a better analgesic effect than those with G allele variants (AG or GG genotypes). Pre-treatment and post-treatment VAS scores for patients with G allele variants were 3.1 and 2.6, respectively; however, for patients with AA genotype, pre-treatment and post-treatment VAS scores were 3.0 and 0.9, respectively (P < .001). The requirement for rescue analgesia was also higher for patients with G allele variants (P = .01). These data suggest that Ultracet is effective in the management of oxaliplatin-induced painful neuropathy. A118G polymorphism of OPRM1, by altered function of the mu-opioid receptor and consequential analgesic effect on opioid agents, could be a key determinant for decreased response to Ultracet.

Epidural Analgesia for Labor and Delivery

A 30-year-old pregnant woman is undergoing induction of labor and is experiencing severe pain despite intravenous opioid administration. Epidural analgesia is recommended. Epidural analgesia involves the injection of a local anesthetic agent and an opioid analgesic agent into the lumbar epidural space. These agents diffuse across the dura and act on the spinal nerve roots. Rates of cesarean delivery are not increased with epidural analgesia.

Opioid and Adjuvant Analgesics: Compared and Contrasted

An adjuvant (or co-analgesic) is a drug that in its pharmacological characteristic is not necessarily primarily identified as an analgesic in nature but that has been found in clinical practice to have either an independent analgesic effect or additive analgesic properties when used with opioids. The therapeutic role of adjuvant analgesics (AAs) is to increase the therapeutic index of opioids by a dose-sparing effect, add a unique analgesic action in opioid-resistant pain, or reduce opioid side effects. A notable difference between opioids and AAs is that unlike opioids some AAs are associated with permanent organ toxicity, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) and renal failure. It is impossible to predict in advance in a given individual what opioid dose they may require to control cancer pain. Most AAs have a ceiling effect for their analgesic actions, but often with continued dose-related toxicities and side effects (with the exception of glucocorticoids). The blood levels of opioids (and their metabolites) can be measured with great precision and accuracy. There is sometimes a role for drug blood levels of certain AAs, like tricyclic antidepressants or anticonvulsants when used for neuropathic pain. Age affects metabolism of most opioids. The therapeutic window of opioids is wide, with no ceiling effect. Most AAs (except corticosteroids) have a narrow therapeutic window. Naloxone is a pure opioid antagonist that competes and displaces opioids from their receptor sites. All clinically useful opioids are mu opioid receptor agonists. Not all routes of administration are available to all opioids. Adjuvant analgesics lack the versatility in routes of administration that opioids possess. Dosing flexibility is a major advantage when treating cancer-related pain with opioids. Dose flexibility is much less with AAs than opioids. Unlike opioids, the analgesic response is usually observed within hours to days of attaining an adequate dose with most AAs (1-2 days). Rotation among opioids is a useful therapeutic strategy to improve analgesic response or minimize toxicity. Most AAs are unsuitable for rescue dosing because of their pharmacological characteristics. The mu agonist side effect profile is similar among the different opioid agents, regardless of the route of administration. The appropriate use of AAs will reduce opioid-related side effects. No apparent tolerance to analgesia develops with AAs. Abrupt discontinuation of an opioid after chronic repeated use for more than a few days will cause a withdrawal syndrome of variable severity. Adjuvant analgesics are an essential tool in cancer pain.

The Impact of Parenteral Narcotic Choice in the Development of Acute Chest Syndrome in Sickle Cell Disease

Acute chest syndrome (ACS) represents a serious morbidity and often fatal complication in patients with sickle cell disease. Painful episodes which require hospitalization are most often treated with opioids, which may then influence the development of ACS. Nalbuphine is a parenteral opioid which effectively treats pain and may cause less ACS. This retrospective chart review documented 988 admissions for painful episodes at 2 institutions and recorded the incidence of ACS and opioid used. At the Children's Hospital in St Louis, Missouri, the incidence of ACS in patients treated with morphine alone was 10.8% versus at the Children's Mercy Hospital in Kansas City, Missouri, the incidence was 2.1% for patients treated solely with nalbuphine. When nalbuphine is used alone as the single parenteral opioid agent to treat painful episodes in patients with sickle cell disease, the incidence of ACS is less than when compared with other opioids used to treat pain.

Population pharmacokinetics of nalbuphine after surgery in children

Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain. However, limited data are available on the pharmacokinetics of this drug in children. The aim of this study was to characterize the population pharmacokinetics of nalbuphine in patients with ages ranging from 1 to 11 yr and to identify patient characteristics partially explaining inter-individual variability in nalbuphine pharmacokinetic parameters. Twenty-two children were included in this study. They received nalbuphine after surgery by continuous infusion (loading dose, 0.2 mg kg(-1) over 10 min followed by continuous infusion of 0.8 mg kg(-1) over 24 h). If pain relief was not adequate, 0.1 mg kg(-1) bolus doses were allowed in 10 min. Eleven blood samples were collected per patient. The data were analysed by non-linear mixed-effect modelling with the use of a two-compartment structural model. Twenty patients completed the study. In the final model, the parameter values were standardized for a body weight of 70 kg using an allometric model. Population parameter estimates were: clearance 130 litre h(-1) 70 kg(-1), inter-compartment clearance 75.6 litre h(-1) 70 kg(-1), central volume of distribution 210 litre 70 kg(-1), and peripheral volume of distribution 151 litre 70 kg(-1). In the children of this study, total clearance expressed in litre h(-1) kg(-1) decreased significantly with increasing age and the elimination half-life significantly increased. The allometric power model developed in this study best reflected the data and may be useful for dose adjustment.

Ketamine for perioperative pain management in children: a meta‐analysis of published studies

Balanced analgesia, using both opioid and nonopioids agents, has become the standard care for postoperative pain management. Ketamine, a compound with analgesic and antihyperalgesic properties, has been shown to decrease postoperative pain and opioid requirements in adults. The goal of the present meta-analysis was to investigate postoperative analgesic properties of ketamine in pediatric patients. A comprehensive literature search was conducted to identify clinical trials that used ketamine as a perioperative analgesic compound in children and infants. Outcomes measured were postoperative analgesic consumption, pain intensity and duration of sensory block (when ketamine was used by caudal route) during the postoperative care unit (PACU) stay and the early postoperative period (6-24 h after leaving the operative room). The data from each trial were combined to calculate the pooled odds ratios or standard mean differences and their 95% confidence intervals. Thirty-five randomized, blinded controlled studies were retrieved from the literature. Systemic ketamine was effective in decreasing PACU pain intensity and analgesic requirement but failed to influence early (6-24 h) pain intensity and analgesic requirement. Ketamine administered locally during tonsillectomy, decreased PACU and early (6-24 h) pain intensity and PACU analgesic requirements. Used as an adjuvant for caudal analgesia, ketamine increased the duration of sensory block and PACU analgesic requirement without impacting PACU pain intensity. Ketamine failed to exhibit a postoperative opioid-sparing effect. This meta-analysis found that administration of ketamine was associated with decreased PACU postoperative pain intensity and nonopioid analgesic requirement. However, ketamine failed to exhibit a postoperative opioid-sparing effect.

Pharmacokinetics of a novel liquid controlled release codeine formulation

Codeine is an important opioid anti-tussive agent whose short half-life (2.9 ± 0.7 h) requires that it be administered at 4-h intervals when formulated as a simple aqueous solution. Liquid controlled release codeine formulations such as an older Codipertussin® formulation, which contained codeine bound to an ion exchange resin and coated with a retardant polymer, achieved an equivalent bioavailability when administered every 12 h. An accompanying paper described the development and in vitro characterization of a novel Codipertussin® formulation containing a non-coated codeine:ion exchange resin (Amberlite IR 69 F) complex. In this study, the bioavailability of codeine from this new liquid controlled release formulation was investigated in an open label, single center, randomized, steady-state, cross-over study in healthy male volunteers. Participants received either 69.7 mg codeine as the controlled release liquid form every 12 h or 23.2 mg codeine in solution every 4 h. Controlled release from the suspension of beads protracted the apparent mean half life of codeine from 3.2 h to 8.2 h, while the mean AUC0–12 h was unchanged. In vivo codeine release profiles were further derived by the numerical deconvolution method, using the data from the drug solution as weighting function for the body system. Comparison of the data obtained with the in vitro release data presented in our earlier work showed an acceptable in vitro–in vivo correlation, which was described as in vitro–in vivo relationship, indicating the power of the in vitro method to predict in vivo pharmacokinetic behavior.

Introduction of a remifentanil-based analgo-sedation protocol leads to a reduction of duration of mechanical ventilation and ICU stay in critically ill patients

Conventional sedation strategies in the ICU are based on the use of propofol or benzodiazepines for sedation in combination with morphine or other opioids for analgesia. An alternative strategy is based on analgo-sedation with remifentanil, a potent and very short-acting opioid agent. However, evidence is scarce that such a strategy is more efficacious.

Do methadone and buprenorphine have the same impact on psychopathological symptoms of heroin addicts?

BackgroundThe idea that the impact of opioid agonist treatment is influenced by the psychopathological profile of heroin addicts has not yet been investigated, and is based on the concept of a specific therapeutic action displayed by opioid agents on psychopathological symptoms. In the present report we compared the effects of buprenorphine and methadone on the psychopathological symptoms of 213 patients (106 on buprenorphine and 107 on methadone) in a follow-up study lasting 12 months.MethodsDrug addiction history was collected by means of the Drug Addiction History Rating Scale (DAH-RS) and psychopathological features were collected by means of the Symptom Checklist-90 (SCL-90), using a special five-factor solution. Toxicological urinalyses were carried out for each patient during the treatment period.ResultsNo statistically significant differences were detected in psychopathological symptoms, including 'worthlessness-being trapped', 'somatization', and 'panic-anxiety'. Methadone proved to be more effective on patients characterized by 'sensitivity-psychoticism', whereas buprenorphine was more effective on patients displaying a 'violence-suicide' symptomatology.ConclusionsHeroin-dependent patients with psychiatric comorbidities may benefit from opioid agonist treatment not only because it targets their addictive problem, but also, precisely due to this, because it is effective against their mental disorder too.

The Therapeutic Applications of and Risks Associated With Acetaminophen Use: A Review and Update

In response to the April 2010 U.S. Food and Drug Administration's (FDA's) revision of warning labeling for over-the-counter (OTC) acetaminophen, or N-acetyl-p-aminophenol (APAP), products, the authors reviewed APAP's potential for liver toxicity.The authors reviewed the literature in which investigators examined data related to the epidemiology of APAP-related liver toxicity, studies in which the investigators evaluated the risk factors for its occurrence and case reports. They included articles that were used by the FDA as the basis for establishing the new labeling requirements.Findings from the literature in which investigators have examined the relationship between APAP and liver toxicity indicate several key risk factors. Foremost are the extensive use of one or more APAP-containing compounds (particularly combinations with opioid agents) and the small margin of safety between the therapeutic and toxic doses. Both of these factors lead to unintentional or intentional drug overdose. Concurrent use of alcohol may contribute to hepatotoxicity, but it may be related to behavior rather than biochemical mechanisms involved in liver damage.The widespread use of APAP has contributed to a substantial increase in the number of cases of acute liver toxicity in the United States. Since APAP is a component of many prescription and OTC medications, unintentional overdose can occur.APAP has numerous applications in dentistry, but if it is used conjointly for other conditions, the risk of the patient's experiencing an overdose increases. In the context of recent FDA concerns about the increased incidence of APAP-related liver toxicity, the authors provide recommendations for safe prescribing practices for APAP. Practitioners should caution patients to follow recommended dosage instructions and avoid taking multiple APAP-containing products.

Should the clinical study on opioid-induced cough continue?

Since Bohrer et al. [1] reported in 1990 that administering fentanyl through a central venous catheter induces the cough reflex, it has become well-known that remifentanil and fentanyl used for inducing general anesthesia cause a cough in various types of clinical situations. This has led to many clinical studies [2-4] thus far, and the research paper of Yoo et al. [5] is also included in this group. The proposed mechanisms through which opioids induce a cough are as follows: (1) pulmonary chemoreflex resulting from stimulation of C-fiber receptors (J receptors) [1], (2) stimulation of irritant receptors (rapidly adapting receptors) from deformation of the tracheobrochial wall by tracheal smooth muscle constriction [6], (3) the release of histamine from lung mast cells [7], and (4) the sudden adduction of the vocal cords or supraglottic obstruction by soft tissue caused by opioid-induced muscle rigidity [8]. Based on these mechanisms, many efforts have been made to reduce the cough reflex induced by opioid agents, and it has been reported that terbutaline (a selective beta-2 agonist) [9], salbutamol [7], lidocaine [10], ephedrine [11], clonidine [12], ketamine [13], and dexamethasone [5] are effective in reducing fenanyl-induced cough (FIC) or remifentanil induced cough (RIC). However, Elcock [14] referred to the paper of Hung et al. [2] that was included in the 2010 volume of Anesthesia and raised the question whether fentanyl really induces a cough with such a high frequency (18-65%) in clinical settings. Also, he stated that his experience of using fentanyl clinically (administering 30 mg of propofol when administering 100 ug of fentanyl before inducing anesthesia) did not induce a cough, and that he was perplexed that research on fentanyl-induced cough continues, and that in actuality, it is not problematic except for pediatric patients. As a result, he asserted that it is meaningless to conduct studies on this phenomenon because, at least for adults, the commonly used dosage of fentanyl does not pose any actual problem. There are also recent reports that recommend not administering the medicine because FIC and RIC are temporary and the pre-treatment itself can cause problems [15]. Moreover, there are studies showing good results from adjusting the administration method of fentanyl and remifentanil so that their blood concentration levels increase gradually, because it is the sudden rise of their blood concentration levels that trigger the cough inducing mechanisms. There are also reports of reducing coughs by administering fentanyl slowly [16] or by administering a small amount in advance, so that there is not a sudden increase in concentration [2]. Also, there are studies that coughs are reduced by administering remifentanil in separate doses [17] and by limiting the peak plasma concentration when infusing remifentanil by TCI [18]. The paper of Ambesh et al. [3] that was published in the British Journal of Anesthesia in 2010 also reported significantly reduced cough (32% to 4%) induced by 2.5 ug/kg of fentanyl if a huffing maneuver was done before inducing anesthesia. Thus, fentanyl and remifentanil induced cough can be significantly reduced even without medicinal prevention. The continuous repetition of the same form of clinical study for more than 20 years seems meaningless even though I do not totally agree with Elcock's opinion. I have also published a paper [19] in 1996 reporting that administration of fentanyl to pediatric patients leads to high-dosage dependency and frequent coughs, and administering lidocaine in advance reduces coughs. In 2010 I published a paper about the impact of FIC on endotracheal intubation in pediatric patients [4]. Although many studies have been carried out over decades, the mechanism of FIC or of RIC has not yet been found. Therefore, I believe it is more useful shed light on why a sudden increase in blood concentration induces a cough, instead of conducting studies about reducing its clinical frequency.

Anaphylactic reaction to intravenous diclofenac

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used as an opioid sparing agent for postoperative analgesia. Anaphylaxis due to intravenous diclofenac sodium is very rare. We report a case of anaphylactic reaction to IV diclofenac sodium, occurring postoperatively in a 25-year-old primigravida, the clinical features of which mimicked pulmonary embolism. The rarity, clinical importance and the diagnostic dilemma associated prompted us to report this case.

Eficacia del bloqueo del ganglio impar en dolor pélvico y perineal de etiología ginecológica rebelde a tratamiento médico-quirúrgico

Visceral pain transmitted by fibers of the sympathetic nervous system in the perineal and pelvic area, whether of benign or malignant etiology, can be effectively treated with neurolysis of the ganglion of Walther, also known as the ganglion impar or sacrococcygeus ganglion. Other possible indications for this technique are shooting anal pain and enteritis. This blockade can rarely eliminate somatic pain or neuropathic features. After this technique has been performed, the required dose of opioid and non-opioid analgesic agents is usually substantially reduced, leading to relief of adverse effects and maximizing analgesic action. The performance of this percutaneous technique can be considered to be of low complexity and with minimal side effects. We describe five cases of pelvic, perineal and coccygeal pain of different etiologies and poor response to conventional drug treatment, as well as the response and clinical course of these patients after completion of ganglion impar blockade with radiofrequency, local anesthetics and phenol neurolysis.

In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel μ opioid analgesic with reduced propensity to alter motor function

Opioids are the most effective analgesics for pain management, and efficient pain control is a therapeutic priority. Herein, we describe the synthesis and pharmacological activities of the 5-benzyl analogue of the μ opioid analgesic 14-methoxymetopon (14-MM). The result of the replacement of the 5-methyl in 14-MM with a benzyl group on in vitro opioid receptor binding and functional profiles, and in vivo behavioural properties, i.e. nociception and motor activity, was investigated. In rodent brain membranes, the 5-benzyl derivative showed high affinity at the μ opioid receptor and decreased interaction with δ and κ receptors, hence displaying a similar binding profile as 14-MM. It displayed potent agonist activity in vitro and in vivo. In in vitro guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding assay, it activated G-proteins in rat brain membranes through a μ opioid receptor-mediated mechanism having significantly enhanced potency compared to DAMGO (d-Ala2,Me-Phe4,Gly-ol5]enkephalin), and to the μ opioid agonist morphinans 14-MM, 14-O-methyloxymorphone (14-OMO) and morphine. In vivo, the 5-benzyl analogue of 14-MM elicited dose-dependent and naloxone-sensitive antinociceptive effects in hot-plate and tail-flick tests in mice after subcutaneous (s.c.) administration. Its analgesic potency was comparable to 14-MM, and was 50-fold higher than that of morphine. Contrary to morphine, 14-MM and 14-OMO, no motor dysfunction was produced by the new opioid in the mouse rotarod test at any of the tested doses. In summary, the 5-benzyl analogue of 14-MM emerged as a novel potent μ opioid antinociceptive agent with reduced propensity to cause unwanted motor impairment.

Tapentadol immediate-release for acute pain

Tapentadol is a novel opioid agent with a dual mode of analgesic action. The inhibition of norepinephrine combined with moderate opioid agonist activity results in fewer gastrointestinal adverse effects compared with equianalgesic doses of oxycodone. Having no active metabolites and minimal protein binding, tapentadol provides improved tolerability with a lower potential for pharmacokinetic drug–drug interactions or accumulation with impaired renal or hepatic function when compared with oxycodone. Tapentadol immediate-release is currently US FDA approved for moderate-to-severe acute pain in adults.