Role of oxycodone and oxycodone/naloxone in cancer pain management

Oxycodone is a valued opioid analgesic, which may be administered either as the first strong opioid or when other strong opioids are ineffective. In case of insufficient analgesia and/or intense adverse effects such as sedation, hallucinations and nausea/vomiting a switch from another opioid to oxycodone might be beneficial. Oxycodone is administered to opioid-naive patients with severe pain and to patients who were unsuccessfully treated with weak opioids, namely tramadol, codeine and dihydrocodeine. Oxycodone effective analgesia may be attributed to its affinity to μ and possibly κ opioid receptors, rapid penetration through the blood-brain barrier and higher concentrations in brain than in plasma. Oxycodone displays high bioavailability after oral administration and may be better than morphine in patients with renal impairment due to the decreased production of active metabolites. Recently an oral controlled-release oxycodone formulation was introduced in Poland. Another new product that was launched recently is a combination of prolonged-release oxycodone with prolonged-release naloxone (oxycodone/naloxone tablets). The aim of this review is to outline the pharmacodynamic and pharmacokinetic properties, drug interactions, dosing rules, adverse effects, equianalgesic dose ratio with other opioids and clinical studies of oxycodone in patients with cancer pain. The potential role of oxycodone/naloxone in chronic pain management and its impact on the bowel function is also discussed.     

CYP2D6‐Inhibiting Drugs and the Increased Risk of Fall‐Related Injuries Due to Newly Initiated Opioid Treatment – A Swedish,Register‐Based Case‐Crossover Study

It has been shown that newly initiated opioid therapy increases the risk of fall‐related injuries. Yet, it remains to be determined whether drug–drug interactions can affect this negative effect, for instance with drugs inhibiting cytochrome P4502D6 (CYP2D6) that metabolizes codeine and also has a partial effect on tramadol and oxycodone. Our aim was to investigate how CYP2D6‐inhibiting drugs contribute to explaining the risk of fall‐related injuries for newly initiated opioid treatments with codeine, tramadol or oxycodone. Data from a Swedish national case‐cross over study were revisited. This study identified a total of 167,257 fall‐related injuries leading to hospitalization that occurred between 1 May 2006 and 31 December 2009 and linked information about dispensed drugs to them. Use of newly dispensed opioids in the 28 days before fall‐related injury with and without CYP2D6‐inhibiting drugs was compared with an earlier control period. For codeine, there was a two‐times increased risk with concomitant CYP2D6‐inhibiting drug use (OR, 1.76; 95% CI 1.40–2.20) and a three‐times risk increase without (OR, 3.17; 95% CI 2.88–3.50). For tramadol, the risks were doubled when CYP2D6‐inhibiting drugs were used (OR, 2.19; 95% CI 1.84–2.60) and tripled without their use (OR, 3.04; 95% CI 2.82–3.27). The risks were about the same for oxycodone, morphine, fentanyl and buprenorphine irrespective of CYP2D6‐inhibiting drug use. In newly initiated opioid therapies, drug–drug interactions from concomitant use of CYP2D6‐inhibiting drugs are associated with a lower risk of fall‐related injury for codeine and tramadol that undergo metabolism via CYP2D6, but not for other opioids.     

In vivo profiling of seven common opioids for antinociception,constipation and respiratory depression: no two opioids have the same profile

BACKGROUND AND PURPOSE

For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.

EXPERIMENTAL APPROACH

Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine^2,5]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively.

KEY RESULTS

These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose–response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.

CONCLUSION AND IMPLICATIONS

For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of ‘opioid rotation’.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Pharmacokinetic-pharmacodynamic modeling in acute and chronic pain: an overview of the recent literature

In acute and chronic pain, the objective of pharmacokinetic-pharmacodynamic (PKPD) modeling is the development and application of mathematical models to describe and/or predict the time course of the pharmacokinetics (PK) and pharmacodynamics (PD) of analgesic agents and link PK to PD. Performing population PKPD modeling using nonlinear mixed effects modeling allows, apart from the estimation of fixed effects (the PK and PD model estimates), the quantification of random effects as within- and between-subject variability. Effect-compartment models and mechanism-based biophase distribution models that incorporate drug-association and -dissociation kinetics are applied in PKPD modeling of pain treatment. Mechanism-based models enable the quantification of the rate-limiting factors in drug effect owing to drug distribution versus receptor kinetics (since receptor kinetics are nonlinear they are discernable from the linear effect-compartment kinetics). It is a helpful technique in understanding the complex behavior of specific analgesics, such as buprenorphine, but also morphine and its active metabolite morphine-6-glucuronide, especially with respect to the reversal of opioid-induced side effects, most importantly life-threatening respiratory depression. One approach in chronic pain studies is the application of mixture models. Mixture models do not necessarily need to take PK data into account and allow the objective differentiation of measured responses to analgesics into specific response subgroups, and as such, may play an important role in analyzing Phase I and II analgesia studies. Appropriate application of PKPD modeling leads to the improvement of current therapeutics with respect to dose design and outcome, understanding the interaction of analgesics within complex chronic pain disease processes and may play an important role in drug development. In the current article, novel observations using the aforementioned techniques on opioids, NSAIDs, epidural analgesia, ketamine and GABA-ergic drugs in acute and chronic pain are discussed.     

A preclinical comparison between different opioids: antinociceptive versus adverse effects

Reduced side-effect liability of opioids may enhance the patient's quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO(2) was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance. ED(50)'s for the occurrence of side-effects were compared to ED(50)'s in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED(50)'s. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.     

口服氨酚羟考酮和盐酸曲马多治疗妇科腹腔镜手术后早期疼痛的研究

目的 :观察妇科腹腔镜手术病人术后早期单次口服氨酚羟考酮 (泰勒宁 )和盐酸曲马多 (奇曼丁 )进行镇痛的有效性和安全性。方法 :12 0例VAS评分 >3分的妇科腹腔镜手术病人 ,随机分 3组 ,分别口服泰勒宁、奇曼丁或安慰剂 1片 ,3组病人均给予吗啡静脉自控止痛泵作为补救镇痛用药。观察并记录服药即刻、服药后 0 .2 5、0 .5、0 .75、1、2、4、6、8、12、2 4h的VAS评分、PCA用量以及不良反应 ,根据VAS评分计算疼痛缓解度 ,2 4h进行总体镇痛满意度评估。结果 :泰勒宁组和奇曼丁组VAS评分低于安慰剂组 (P <0 .0 5 ) ,泰勒宁组和奇曼丁组之间VAS评分相近 (P >0 .0 5 )。泰勒宁组和奇曼丁组补救PCA吗啡用量明显低于安慰剂组 (P <0 .0 5 ) ,泰勒宁组和奇曼丁组补救PCA吗啡用量相当 (P >0 .0 5 )。泰勒宁组和奇曼丁组总体镇痛满意度评估优于安慰剂组 (P <0 .0 5 )。 2 4h恶心呕吐率方面 ,奇曼丁组明显高于其他两组 (P <0 .0 5 )。结论 :口服泰勒宁和奇曼丁能有效地缓解妇科腹腔镜病人手术后的中至重度疼痛 ,早期口服给药镇痛的方式安全、有效。与奇曼丁组相比 ,泰勒宁组的不良反应发生率更低。     

Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model

Analgesia from most opioids is mediated by mu receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic/pharmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty-four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood samples and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic/pharmacodynamic profiles were modeled using a 2-stage, nonlinear, mixed-effects approach with an effect compartment to represent the concentration-analgesia delay. Morphine kinetics was best described by a 2-compartment model, whereas oxycodone kinetics was best described with a 1-compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic/pharmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.     

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder

Background: There is a paucity of published literature on the optimal treatment of pain in patients on buprenorphine treatment (BT) for opioid use disorder. Using this case report, we hope to demonstrate that tramadol may represent an effective treatment option for pain in patients on BT while encouraging future clinical trials. Case: The patient is a 56-year-old Caucasian male with a history of opiate use disorder on treatment with buprenorphine/naloxone 8/2?mg 2 times a day (BID) who was followed in an outpatient general psychiatry clinic that specializes in patients with co-occurring substance use disorders. Although maintaining sobriety from opioids, the patient continued to struggle with acute on chronic pain secondary to osteoarthritis that had left him walking with a cane. The patient was started on tramadol 50?mg 3 times a day (TID) for acute pain by his primary care physician (PCP) while he awaited surgical intervention. He reported analgesic effect with buprenorphine/naloxone but noted that it did not last the full period between his doses. He reported further improvement in his pain along with greater daily functioning with the additional use of tramadol, without side effects or withdrawal symptoms. Discussion: Current recommendations for pain management in patients on BT include discontinuation of BT therapy and/or addition of an adjunctive opioid analgesic (including additional buprenorphine/naloxone) while continuing agonist medication for treatment of opioid use disorder. However, determining which medication to use can be difficult, as there has been no literature examining this issue. In this case, the combination of buprenorphine and tramadol demonstrated an additive analgesic effect. Randomized control studies need to be performed to further understand the changes in pain measurement in patients on BT with tramadol compared with other adjunctive analgesic medications.     

Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model

Objective: The relative analgesic potency of single doses of oral controlled-release oxycodone and oral controlled-release morphine were compared in a randomized, double-blind trial using a postoperative pain model. Methods: Women (n = 169) with moderate to severe pain following abdominal hysterectomy received single oral doses of controlled-release oxycodone, 20 mg or 40 mg, or controlled-release morphine, 45 mg or 90 mg. Assessments were made at 30 min, 60 min, then hourly after dosing for 12 h or until remedication. Results: The most precise estimates of relative potency showed that controlled-release oxycodone was 1.8 times more potent than controlled-release morphine for total effect (95% confidence limits 1.09–2.42; lambda 0.44) and 2.2 times more potent for peak effect (95% confidence limits 0.96–4.59; lambda 0.71). Controlled-release oxycodone at doses of 20 mg or 40 mg was comparable with controlled-release morphine at doses of 45 mg or 90 mg, respectively, for total and peak analgesic effects. For the two higher doses, time to peak relief was approximately 1 h shorter with controlled-release oxycodone than with controlled-release morphine. Most patients reported onset of analgesia within 1 h with all doses. Side effects were similar with the two opioids. Conclusion: Oral controlled-release oxycodone was twice as potent as oral controlled-release morphine in this single-dose, relative potency assay. When converting patients from oral morphine to oral oxycodone, an initial oral oxycodone dose of one-half the oral morphine dose is recommended. Received: 10 August 1998 / Accepted in revised form: 9 March 1999     

Intrathecal injection of codeine, buprenorphine, tilidine, tramadol and nefopam depresses the tail-flick response in rats

The effect of intrathecal (i.t.) injection of the analgesic agents, codeine, buprenorphine, tilidine and one of its metabolites, nortilidine, tramadol and nefopam, was determined in the tail-flick test performed on rats. ED50 values were derived from the dose-response lines. The relative potency ranking established from the ED50 values is buprenorphine (0.4 nM) greater than nortilidine (29 nM) = tramadol (26 nM) = nefopam (34 nM) greater than codeine (42 nM) greater than tilidine (118 nM). An i.t. injection of the opiate antagonist, naloxone (5 micrograms), prevented the antinociceptive effect of all analgesic agents administered at the highest dose tested. It is concluded that these analgesic agents, like morphine, exert their effect at least in part through a spinal site of action.     

Pharmacokinetics of opioids in liver disease.

The liver is the major site of biotransformation for most opioids. Thus, the disposition of these drugs may be affected in patients with liver insufficiency. The major metabolic pathway for most opioids is oxidation. The exceptions are morphine and buprenorphine, which primarily undergo glucuronidation, and remifentanil, which is cleared by ester hydrolysis. Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in decreased drug clearance [for pethidine (meperidine), dextropropoxyphene, pentazocine, tramadol and alfentanil] and/or increased oral bioavailability caused by a reduced first-pass metabolism (for pethidine, dextropropoxyphene, pentazocine and dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, and clearance of morphine was found to be decreased and oral bioavailability increased. The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administration. Lower doses or longer administration intervals should be used to remedy this risk. Special risks are known for pethidine, with the potential for the accumulation of norpethidine, a metabolite that can cause seizures, and for dextropropoxyphene, for which several cases of hepatotoxicity have been reported. On the other hand, the analgesic activity of codeine and tilidine depends on transformation into the active metabolites, morphine and nortilidine, respectively. If metabolism is decreased in patients with chronic liver disease, the analgesic action of these drugs may be compromised. Finally, the disposition of a few opioids, such as fentanyl, sufentanil and remifentanil, appears to be unaffected in liver disease.     

The analgesic effect of etoricoxib relative to that of two opioid-acetaminophen analgesics: a randomized,controlled single-dose study in acute dental impaction pain

ABSTRACT

Background: To compare the analgesic effect of single doses of etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg in acute pain using the dental impaction model.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6?h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences.

Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg, codeine/acetaminophen 60?mg/600?mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2?units) versus oxycodone/acetaminophen (10.2?units); and codeine/acetaminophen (6.0?units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (?p < 0.001) shorter for oxycodone/acetaminophen (20?min) and numerically but not significantly shorter (?p = 0.259) for codeine/acetaminophen (26?min) compared with etoricoxib (40?min). Etoricoxib (24?h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3?h), codeine/acetaminophen (2.7?h), and placebo (1.7?h) (?p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (?p < 0.05) fewer episodes of nausea.

Conclusion: Etoricoxib 120?mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg.     

G protein-gated inwardly rectifying potassium (KIR3) channels play a primary role in the antinociceptive effect of oxycodone,but not morphine,at supraspinal sites

BACKGROUND AND PURPOSE

Oxycodone and morphine are μ-opioid receptor agonists prescribed to control moderate-to-severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein-gated inwardly rectifying potassium (K_IR3 also known as GIRK) channels in their antinociceptive effects.

EXPERIMENTAL APPROACH

Opioid-induced antinociceptive effects were assessed in mice, using the tail-flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of K_IR3.1 channels with tertiapin-Q (30 pmol per mouse, i.c.v. and i.t.) and K_IR3.1-specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration in the mouse femur bone cancer and neuropathic pain models.

KEY RESULTS

The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by K_IR3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by K_IR3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin-Q.

CONCLUSION AND IMPLICATIONS

These results demonstrate that K_IR3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal K_IR3.1 channels are responsible for the unique analgesic profile of oxycodone.     

Opioid agonist-antagonist drugs in acute and chronic pain states.

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak mu-antagonists and kappa-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the mu-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2 micrograms tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Section Review Central & Peripheral Nervous Systems: Pharmacological Modulation of Opioid Tolerance

Although tolerance to opioids probably involves a variety of mechanisms, in vivo studies suggest a prominent role for the NMDA/nitric oxide cascade. Administration of NMDA antagonists blocks the development of tolerance to morphine and the delta opioid [D-Pen², D-Pen⁵]enkephalin without interfering with their analgesic actions, indicating the dissociation of analgesia and tolerance. Similar effects are observed with competitive and noncompetitive antagonists, as well as agents modulating NMDA function through its glycine regulatory site. Inhibitors of nitric oxide synthase have similar actions, suggesting the presence of an NMDA/nitric oxide cascade. This conclusion is supported by the ability of L-arginine, the substrate for nitric oxide synthase, to enhance morphine tolerance by increasing the production of nitric oxide. Tolerance to kappa analgesic systems behaves differently. In most studies, neither kappa₁ nor kappa₃ opioid tolerance is influenced by these drugs. This ability to modulate opioid tolerance has important clinical implication, in addition to providing insights into the mechanisms of analgesia and tolerance.     

μ-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons

BACKGROUND AND PURPOSE

Tapentadol is a novel analgesic that combines moderate μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. Both mechanisms of action are involved in producing analgesia; however, the potency and efficacy of tapentadol in individual neurons has not been characterized.

EXPERIMENTAL APPROACH

Whole-cell patch-clamp recordings of G-protein-coupled inwardly rectifying K⁺ (K_IR3.x) currents were made from rat locus coeruleus neurons in brain slices to investigate the potency and relative efficacy of tapentadol and compare its intrinsic activity with other clinically used opioids.

KEY RESULTS

Tapentadol showed agonist activity at μ receptors and was approximately six times less potent than morphine with respect to K_IR3.x current modulation. The intrinsic activity of tapentadol was lower than [Met]enkephalin, morphine and oxycodone, but higher than buprenorphine and pentazocine. Tapentadol inhibited the noradrenaline transporter (NAT) with potency similar to that at μ receptors. The interaction between these two mechanisms of action was additive in individual LC neurons.

CONCLUSIONS AND IMPLICATIONS

Tapentadol displays similar potency for both µ receptor activation and NAT inhibition in functioning neurons. The intrinsic activity of tapentadol at the μ receptor lies between that of buprenorphine and oxycodone, potentially explaining the favourable profile of side effects, related to μ receptors.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Pharmacokinetic and Pharmacodynamic Modeling of Opioid-Induced Gastrointestinal Side Effects in Patients Receiving Tapentadol IR and Oxycodone IR

Purpose

To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.

Methods

The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.

Results

Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3?C4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.

Conclusions

This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.