Comparative pharmacological profiles of oxycodone and morphine in a neuropathic pain-like state in mice

According to the World Health Organization (WHO) guidelines for cancer patients with moderate or severe pain, morphine is the standard treatment for cancer pain. However, the use of morphine is sometimes accompanied by side effects such as constipation, emesis and drowsiness. Oxycodone, a series of opioids, interacts primarily with the μ-opioid receptor and has been used for opioid rotation. In the clinic, oxycodone has been used for pain management since 1917 and is widely acknowledged as an invaluable alternative to morphine. This review aims to compare the pharmacological profiles of oxycodone and morphine in a neuropathic pain-like state in mice.     

Distinct relations among plasma concentrations required for different pharmacological effects in oxycodone, morphine, and fentanyl

Several clinical reports showed that adverse effect profiles are not the same in morphine, oxycodone, and fentanyl. The authors investigated whether the relationship between plasma concentrations for antinociceptive effect and for various pharmacological effects differed among oxycodone, morphine, and fentanyl under controlled experimental setting using animal models. Oxycodone induced constipation and an antinociceptive effect in a similar concentration-dependent manner, whereas morphine required approximately 9-fold higher plasma concentration for antinociceptive effect compared with that for constipation when 50% effective plasma concentration (EC(50)) levels were compared. The EC(50) values for inhibition of behavioral activity were 2.1-, 2.7-, and 1.3-fold higher than those for antinociceptive effect in oxycodone, morphine, and fentanyl, respectively. Respiratory inhibition was observed even at higher plasma concentrations in all three opioids, and the differences in the EC(50) values compared with those for antinociceptive effects were 234.5-fold (oxycodone), 233.1-fold (morphine), or 104.2-fold (fentanyl). These results showed that oxycodone, morphine, and fentanyl exhibited unique patterns of plasma concentrations required for different pharmacological effects. The different adverse effect profiles observed in a clinical setting appear to be resulted from, at least in part, distinct intrinsic pharmacological profiles among these μ-opioid receptor agonists.     

镇痛药物及其应用

镇痛药物是医生们进行疼痛治疗的重要工具。镇痛药物根据作用机制可分为阿片类镇痛药、非阿片类镇痛及辅助性镇痛药。阿片类镇痛药以吗啡、芬太尼等为代表药物,近来其他人工合成的可待因衍生物如羟可酮、氢可酮等也逐渐被用于临床。非阿片类镇痛药物主要包括非甾体类抗类药,其中环氧化酶-2抑制剂如塞来昔布等高选择抑制剂具有副作用较小的优点。此外氯胺酮、可乐定等非阿片类药物的镇痛作用近来也被重新研究和应用。辅助性镇痛药物以抗惊厥、抗精神病药物为主,对于阿片类药物不敏感的患者,可作为辅助用药。     

Distinct Relations Among Plasma Concentrations Required for Different Pharmacological Effects in Oxycodone,Morphine, and Fentanyl

ABSTRACT

Several clinical reports showed that adverse effect profiles are not the same in morphine, oxycodone, and fentanyl. The authors investigated whether the relationship between plasma concentrations for antinociceptive effect and for various pharmacological effects differed among oxycodone, morphine, and fentanyl under controlled experimental setting using animal models. Oxycodone induced constipation and an antinociceptive effect in a similar concentration-dependent manner, whereas morphine required approximately 9-fold higher plasma concentration for antinociceptive effect compared with that for constipation when 50% effective plasma concentration (EC₅₀) levels were compared. The EC₅₀ values for inhibition of behavioral activity were 2.1-, 2.7-, and 1.3-fold higher than those for antinociceptive effect in oxycodone, morphine, and fentanyl, respectively. Respiratory inhibition was observed even at higher plasma concentrations in all three opioids, and the differences in the EC₅₀ values compared with those for antinociceptive effects were 234.5-fold (oxycodone), 233.1-fold (morphine), or 104.2-fold (fentanyl). These results showed that oxycodone, morphine, and fentanyl exhibited unique patterns of plasma concentrations required for different pharmacological effects. The different adverse effect profiles observed in a clinical setting appear to be resulted from, at least in part, distinct intrinsic pharmacological profiles among these μ-opioid receptor agonists.     

Normal-release and controlled-release oxycodone: pharmacokinetics,pharmacodynamics, and controversy

Oxycodone has become one of the most popular opioids in the United States. It is superior to morphine in oral absorption and bioavailability, and similar in terms of protein binding and lipophilicity. Gender more than age influences oxycodone elimination. Unlike morphine, oxycodone is metabolized by the cytochrome isoenzyme CYP2D6, which is severely impaired by liver dysfunction. Controlled-release (CR) oxycodone has become one of the most frequently utilized sustained-release opioids in the United States. Both its analgesic benefits and its side effects are similar to those of CR morphine. CR oxycodone is similar to morphine and other opioids in its abuse potential. Deaths attributable to oxycodone are usually associated with polysubstance abuse in which oxycodone is combined with psychostimulants, other opioids, benzodiazepines or alcohol. Oxycodone's kappa receptor binding has little role in abuse or addiction. The cost of CR oxycodone is prohibitive for most American hospices.     

Differential therapeutic aspects of analgesia with oral sustained-release strong opioids: application intervals, metabolism and immunosuppression

The oral "around-the clock" administration of sustained-release strong opioids has been recommended for the long-term treatment of patients suffering from chronic severe pain. At present a plethora of products are available in Germany. Modern galenics even allow for only once-daily oral application without clinically relevant negative chronobiological interference. This application scheme has been shown to improve compliance and sleep quality, factors that influence treatment outcome. Randomized controlled studies revealed no relevant differences between the different strong opioids with respect to efficacy and tolerability. However, hydromorphone and oxycodone appear to be advantageous over morphine due to a lack of immunosuppression. Hydromorphone has the additional benefit of a lower risk of intoxication by accumulation of active metabolites in patients with decreased renal function. As a result, although morphine has been regarded as the standard for the treatment of chronic severe pain, hydromorphone and oxycodone may be better and safer alternatives for certain patient groups (e.g. older age, multimorbidity, cancer).     

Differenzialtherapeutische Aspekte in der Schmerztherapie mit retardierten, oralen, stark wirksamen Opioiden

The oral “around-the clock” administration of sustained-release strong opioids has been recommended for the long-term treatment of patients suffering from chronic severe pain. At present a plethora of products are available in Germany. Modern galenics even allow for only once-daily oral application without clinically relevant negative chronobiological interference. This application scheme has been shown to improve compliance and sleep quality, factors that influence treatment outcome. Randomized controlled studies revealed no relevant differences between the different strong opioids with respect to efficacy and tolerability. However, hydromorphone and oxycodone appear to be advantageous over morphine due to a lack of immunosuppression. Hydromorphone has the additional benefit of a lower risk of intoxication by accumulation of active metabolites in patients with decreased renal function. As a result, although morphine has been regarded as the standard for the treatment of chronic severe pain, hydromorphone and oxycodone may be better and safer alternatives for certain patient groups (e.g. older age, multimorbidity, cancer).     

Dose-response relationship after single oral dose administrations of morphine and oxycodone using laser-evoked potentials on UVB- and capsaicin-irritated skin in healthy male subjects

The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of ≥ 2.5 μV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids.     

Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief

Breakthrough pain is a common and distinct component of cancer pain that is usually managed with normal release opioids (also known as rescue medication) either before or soon after its onset. A prospective survey of hospice inpatients with breakthrough pain was undertaken to characterize their pain and then compare the time to onset of pain relief of their rescue medication. Patients presented with, on average, 1.7 different types of breakthrough pains (range, 1–4). The average number of breakthrough pains was four per day (range, 1–8), and the average duration of breakthrough pain was 35 minutes (range, 15–60); most occurred suddenly and unpredictably. Patients used morphine, oxycodone, hydromorphone, methadone, or oral transmucosal fentanyl citrate as rescue medication and the average time to meaningful pain relief following their administration was 31 minutes (range, 5–75). No difference was found between morphine, oxycodone, and hydromorphone. Methadone appeared to work faster than morphine (P < 0.01) but no faster than oxycodone or hydromorphone, whereas oral transmucosal fentanyl citrate worked faster than morphine, oxycodone, hydromorphone, and methadone (P < 0.001).     

Efficacy of oxycodone/paracetamol for patients with bone-cancer pain: a multicenter, randomized, double-blinded, placebo-controlled trial

What is known and Objective: Bone‐cancer pain is a common and refractory cancer pain. Opioids, on their own, do not control this type of pain well enough, and co‐analgesics are necessary. Methods: Patients with bone metastasis‐related pain at Numeric Rating Scale ≥4 were enrolled to this randomized placebo‐controlled trial. They had also received morphine or transdermal fentanyl patches for at least 1 week. During the 3‐day efficacy phase, patients received placebo or 1–3 tablets of oxycodone/paracetamol (5/325 mg), four times daily for 3 days. All patients kept a daily pain diary. The primary endpoint was the Pain Intensity Difference (PID). Secondary endpoints were cases of breakthrough pain and rescue morphine consumption. Additional analyses included the Short Form‐6 Dimensions (SF‐6D) quality‐of‐life scale and a general impression (GI) of patient satisfaction with treatment at the end of the phase. Results and Discussion: Of the 246 patients in the intent‐to‐treat set, 89·4% completed the 3‐day efficacy phase. PIDs were 0·9 and 0·3 in the oxycodone/paracetamol and placebo groups respectively, on day 1 (P < 0·001), and 1·5 and 0·3 respectively on day 3 (P < 0·001). Thirty‐eight patients in the treatment group, and 58 in the placebo group, suffered breakthrough pain on day 3 (P < 0·001). The SF‐6D score decreased to 21·2 ± 2·5 in the oxycodone/paracetamol group at the end of the phase (P = 0·001). In the oxycodone/paracetamol group, 67% rated GI as good, very good, or excellent. What is new and Conclusion: Patients with bone‐cancer pain, already on opioids, obtain clinically important, additional pain‐control, with regular oxycodone/paracetamol dosing.     

Incidence of constipation associated with long-acting opioid therapy: a comparative study

BACKGROUND: Opioid therapy plays a key role in the management of chronic pain. Constipation is one of the more frequently occurring adverse effects associated with opioid therapy. METHODS: A retrospective cohort design study was conducted to determine the incidence of constipation in chronic pain patients who received three different long-acting opioids (transdermal fentanyl, oxycodone HCl controlled-release [CR], or morphine CR) for malignant or nonmalignant chronic pain. The data source was claims data (January 1996 through March 2001) from a 20% random sample of the California Medicaid (Medi-Cal) database. Claims data were from adult patients with chronic pain (malignant or nonmalignant) who had no prior diagnosis of constipation and no prior usage of long-acting opioids for at least 3 months before the observation period. Patients were followed for at least 3 months after the initiation of opioid therapy. ICD-9 code for diagnosis of constipation was the main outcome variable. Crude rates of constipation, annual incidence density, relative risk, and adjusted odds ratios were compared. RESULTS: A total of 1,836 patients (601 receiving transdermal fentanyl, 721 receiving oxycodone CR, and 514 receiving morphine CR) were included in the analysis. Crude (unadjusted) rates of constipation were 3.7% for transdermal fentanyl, 6.1% for oxycodone CR, and 5.1% for morphine CR (P > 0.05). Transdermal fentanyl had a lower annual incidence density and risk of constipation than oxycodone CR and morphine CR (P > 0.05). After adjusting for confounding variables, including race and supplemental opioid use, the adjusted risk of constipation was 78% greater in the oxycodone CR group (P = 0.0337) and 44% greater in the morphine CR group (P = 0.2242) than in the transdermal fentanyl group. CONCLUSION: In this population, patients receiving transdermal fentanyl had a lower risk of developing constipation compared with those receiving oxycodone CR or morphine CR.     

Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study.

Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p 相似文献   

Morphine and oxycodone hydrochloride in the management of cancer pain

In a double-blind crossover study, morphine and oxycodone hydrochloride were administered to 20 patients who were experiencing severe cancer pain. The peroral doses were determined on the basis of patient-controlled intravenous titration. The assumed oral bioavailability ratios were 44% (group 1, first 10 patients) and 33% (group 2, last 10 patients) for morphine and 66% (group 1) and 50% (group 2) for oxycodone hydrochloride, respectively. However, the patients were able to readjust their oral dosings. Equal analgesia was achieved with both drugs, but the intravenous dose of oxycodone hydrochloride needed was 30% higher than that of morphine. The median calculated oral/intravenous ratios giving comparable analgesia were 0.31 for morphine and 0.70 for oxycodone hydrochloride. Morphine caused more nausea than oxycodone hydrochloride and hallucinations occurred only during morphine treatment. Otherwise, there were no major differences in the side effects between these two opioids.     

Efficacy and safety of oxymorphone extended release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study.

This multicenter, randomized, double-blind, placebo- and active-controlled trial was conducted to compare the analgesic efficacy and safety of oxymorphone extended release (ER) with placebo and oxycodone controlled release (CR) in ambulatory patients with moderate to severe chronic low back pain requiring opioid therapy. Patients (N = 213) aged 18 to 75 years were randomized to receive oxymorphone ER (10 to 110 mg) or oxycodone CR (20 to 220 mg) every 12 hours during a 7- to 14-day dose-titration phase. Patients achieving effective analgesia at a stable opioid dose entered an 18-day double-blind treatment phase and either continued opioid therapy or received placebo. With stable dosing throughout the treatment phase, oxymorphone ER (79.4 mg/day) and oxycodone CR (155 mg/day) were superior to placebo for change from baseline in pain intensity as measured on a visual analog scale; the LS mean differences were -18.21 and 18.55 (95% CI, -25.83 to -10.58 and -26.12 to -10.98, respectively; P = .0001). Use of rescue medication was 20 mg per day. Adverse events for the active drugs were similar; the most frequent were constipation and sedation. Oxymorphone ER and oxycodone CR were generally safe and effective for controlling low back pain. Oxymorphone ER was equianalgesic to oxycodone CR at half the milligram daily dosage, with comparable safety. PERSPECTIVE: Definitive studies of long-acting opioids in patients with chronic low back pain are lacking. We report the results of a multicenter, randomized, placebo-controlled, double-blind study evaluating the analgesic efficacy and safety of oxymorphone ER and oxycodone CR in opioid-experienced patients with chronic low back pain.     

Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers.

In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain. PERSPECTIVE: Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.     

Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy

BACKGROUND: Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve.METHODS: Patients with diabetic neuropathy with moderate or greater pain for at least 3 months, were evaluated for efficacy, safety and health-related quality of life (QOL) while receiving controlled-release (CR) oxycodone (OxyContin) or active placebo. Patients underwent washout from all opioids 2-7 days before randomization to 10 mg CR oxycodone or active placebo (0.25 mg benztropine) q12h. The dose was increased, approximately weekly, to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine, with crossover to the alternate treatment after a maximum of 4 weeks. Acetaminophen, 325-650 mg q4-6h prn was provided as rescue.RESULTS: Thirty-six patients were evaluable for efficacy (21 men, 15 women, mean age 63.0+/-9.4 years). CR oxycodone resulted in significantly lower (P=0.0001) mean daily pain (21.8+/-20.7 vs. 48.6+/-26.6 mm VAS), steady pain (23.5+/-23.0 vs. 47.6+/-30.7 mm VAS), brief pain (21.8+/-23.5 vs. 46.7+/-30.8 mm VAS), skin pain (14.3+/-20.4 vs. 43.2+/-31.3 mm VAS), and total pain and disability (16.8+/-15.6 vs. 25.2+/-16.7; P=0.004). Scores from 6 of the 8 SF-36 domains and both summary scales, Standardized Physical Component (P=0.0002) and Standardized Mental Component (P=0.0338) were significantly better during CR oxycodone treatment. The number needed to treat to obtain one patient with at least 50% pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo (P=0.0001).CONCLUSION: CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL.     

Translational human pain research

Human experimental pain models require standardized stimulation and quantitative assessment of the evoked responses. This approach can be applied to healthy volunteers and pain patients before and after pharmacological interventions. Standardized stimuli of different modalities (mechanical, chemical, thermal, electrical) can be applied to skin, muscles and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using such a multi-modal, multi-tissue approach, new and existing analgesic drugs can be profiled. Human experimental pain models can bridge animal and clinical pain research and act as translational research providing new possibilities for designing successful clinical trials. Proof-of-concept studies provide cheap, fast and reliable information about dose-efficacy relationships and how pain from skin, muscles and viscera are inhibited. This is important knowledge to have prior to designing expensive clinical trials.     

Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.     

The role of hydromorphone in cancer pain treatment: a systematic review

The aim of this systematic review is to evaluate the scientific evidence for the efficacy and side effects of hydromorphone in the management of moderate to severe cancer pain. Randomized and non-randomized clinical trials, reporting data on efficacy and/or side effects of hydromorphone, were identified. Thirteen eligible studies, involving 1208 patients, were selected. Seven studies compared hydromorphone with other opioids (five with morphine, one with oxycodone and one with fentanyl and buprenorphine) and five of them were randomized controlled trials (RCTs). Most of the studies were conducted on patients already receiving opioid treatment, often at stabilized doses, and most had methodological limitations. The RCTs comparing hydromorphone with morphine and oxycodone showed similar analgesic results, while the comparison of side effects showed minor differences, not consistent across studies. Due to clinical and methodological heterogeneity of the studies, a meta-analysis was not performed. In conclusion there is evidence to support the efficacy and tolerability of hydromorphone for moderate to severe cancer pain as an alternative to morphine and oxycodone, while there is no evidence to demonstrate its superiority or inferiority in comparison with morphine as the first choice opioid for the same indication.