Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study

SUMMARY

Objective: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain.

Research design and methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (≥ 18?years of age) with moderate or severe cancer pain who were first titrated for 3–10?days with open-label oxymorphone or oxycodone to achieve a stable dose that provided adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7–10?days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue.

Main outcomes and measures: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect.

Results: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores and other efficacy parameters were comparable for the 2 groups. The mean daily dosage of oxycodone CR (91.9?mg) was twice that of oxymorphone ER (45.9?mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15?mg/day). No significant differences in opioid adverse events were observed between the groups.

Conclusions: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72?h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.     

Efficacy and safety evaluation of once-daily OROS hydromorphone in patients with chronic low back pain: a pilot open-label study (DO‑127)

ABSTRACT

Objective: To evaluate the safety, tolerability, and efficacy of once-daily osmotic controlled-release oral delivery system (OROS) hydromorphone in patients with chronic low back pain of moderate-to-severe intensity.

Research design and methods: This was a 6-week, multicenter, nonrandomized, noncomparative, open-label, repeat-dose study of chronic (≥?6 weeks) low back pain. The study comprised three periods: prior opioid stabil­ization (2–7 days); OROS hydromorphone conversion, titration, and stabilization (3–14 days); and OROS hydro­morphone maintenance (28 days). Patients were evalu­ated weekly. Baseline pain assessment was performed at the end of prior opioid stabilization. For pain relief rating, endpoint was defined as the mean pain relief score from the last 2 nonmissing days before study termination. For other assessments, endpoint was defined as the last post-baseline evaluation.

Results: Of the 207 patients who received the study drug, 131 completed the trial. Scores (mean ± SD) for Brief Pain Inventory ‘worst pain in the last 24 hours’ decreased significantly from baseline to endpoint (–0.8 ± 2.06, p < 0.0001). The proportions of patients and investigators rating the global effectiveness as good, very good, or excellent increased from 31.6% at baseline while patients were on prior opioids to 63.2% at endpoint while patients received OROS hydromorphone, and from 29.8% at baseline while patients were on prior opioids to 65.8% at endpoint while patients received OROS hydromorphone, respectively. Daily pain relief ratings also increased significantly (+0.26 ± 1.084, p = 0.0008). Significant improvements in health-related quality of life and sleep problems were observed. Adverse events were mild to moderate in severity; the most common of these were constipation, nausea, headache, and somnolence. The limitations of this study include its pilot-type design and the lack of comparison of OROS hydromorphone with a placebo or another drug. Additional comparative and longer-term studies are needed to confirm these findings.

Conclusions: OROS hydromorphone may be an effective treatment for chronic low back pain of moderate-to-severe intensity. Adverse events were typical of those associated with opioid therapy.     

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study

OBJECTIVE: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain. Research design and methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (>or= 18 years of age) with moderate or severe cancer pain who were first titrated for 3-10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided and other efficacy parameters were comparable for adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7-10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue. MAIN OUTCOMES AND MEASURES: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect. RESULTS: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups. CONCLUSIONS: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.     

Hydromorphone-OROS formulation

Importance to the field: Hydromorphone is a semi-synthetic opioid approved in the USA for the treatment and relief of moderate to severe pain and postoperative pain. However, the compound is short-acting, and there is no extended-release formulation clinically available. A previous hydromorphone extended-release formulation that successfully came to market was subsequently withdrawn on account of safety concerns. Clinical need supports the presence of an extended-release formulation of hydromorphone.

Areas covered in this review: Medline articles showing from a search of ‘hydromorphone and OROS’ were included in the review. In addition, searches were done relating to published data regarding regulatory affairs dealing with this specific topic. Physicians prescribing information for hydromorphone was also reviewed.

What the reader will gain: The reader will gain an increased understanding of the use of an extended-release formulation of hydromorphone using the OROS technology and will appreciate that this technology has safety advantages compared with previous extended-release formulations of hydromorphone.

Take home message: Hydromorphone-OROS is an effective agent for the long-acting control of pain and a welcome addition to other available opioid formulations.     

Comparison of the analgesic effect of patient‐controlled oxycodone and fentanyl for pain management in patients undergoing colorectal surgery

Oxycodone is a μ‐opioid receptor agonist and is generally indicated for the relief of moderate to severe pain. The aim of this study was to compare the analgesic efficacy of patient‐controlled oxycodone and fentanyl for postoperative pain in patients undergoing colorectal surgery. Patients scheduled to undergo elective colorectal surgery (n=82) were allocated to receive oxycodone (n=41, concentration of 1 mg/mL) or fentanyl (n=41, concentration of 15 μg/mL) for postoperative pain management. After the operation, pain using a numerical rating scale (NRS), delivery to demand ratio, infused dose of patient‐controlled analgesia (PCA), side effects, and sedation levels were evaluated. Median (25%–75%) cumulative PCA dose of oxycodone group at 48 hours (66.9, 58.4–83.7 mL) was significantly less than that of fentanyl group (80.0, 63.4–103.3 mL, P=.037). Six hours after surgery, the mean (SD) NRS scores of the oxycodone and fentanyl groups were 6.2 (2.4) and 6.8 (1.9), respectively (P=.216). The mean equianalgesic potency ratio of oxycodone to fentanyl was 55:1. The groups did not differ in postoperative nausea, vomiting, and level of sedation. Patient‐controlled oxycodone provides similar effects for pain relief compared to patient‐controlled fentanyl in spite of less cumulative PCA dose. Based on these results, oxycodone can be a useful alternative to fentanyl for PCA in patients after colorectal surgery.     

Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form

ABSTRACT

Background: The osmotic-controlled release oral delivery system, OROS, is an advanced drug delivery technology that uses osmotic pressure as the driving force to deliver pharmacotherapy, usually once-daily, in several therapeutic areas.

Objective: The purpose of this review is to discuss the evolution of OROS technology and examine the many therapeutic areas where OROS products are being used.

Methods: A search of Medline and EMBASE were performed using the keywords ‘OROS’ and ‘osmotic delivery’ for the period January 1990 to June 2005. Data were also obtained from the manufacturers’ websites and associated publications.

Results: OROS technology has evolved over the last 30 years, resulting in four systems: the elementary osmotic pump; the two-layer osmotic push–pull tablet; the advanced longitudinally compressed tablet multilayer formulation; and, the L-OROS system. OROS technology is employed for drug delivery in many therapeutic areas including: cardiovascular medicine, endocrinology, urology, and central nervous system (CNS) therapeutics. Two calcium channel blockers utilizing OROS technology for the treatment of hypertension are nifedipine and verapamil. Glipizide extended-release is used for the treatment of type 2 diabetes. Doxazosin is used for the treatment of benign prostatic hyperplasia, and oxybutynin for overactive bladder. Most recent developments are with drugs that affect the CNS, including the use of methylphenidate for treatment of attention deficit hyperactivity disorder, paliperidone extended-release and OROS hydromorphone, which are under clinical development for schizophrenia and chronic pain, respectively.

Conclusions: Drug delivery using the various OROS products can result in an improved safety profile, stable drug concentrations, uniform drug effects, and reduced dosing frequency. OROS technology has also enabled the use of an effective starting dose, without the need for dose titration, which allows the achievement of symptom control much earlier than that observed with immediate-release preparations. Such attributes can enhance patient compliance and convenience, thereby ensuring efficacy and improving patient outcomes.     

Erratum

Online summary

Correction to: Hale M, et al. Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin 2010;26:1505-18     

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.     

Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain

Abstract

Objective:

This multicenter, double-blind, placebo-controlled study using a randomized withdrawal design evaluated the efficacy and safety of once-daily OROS hydromorphone ER in the treatment of opioid-tolerant patients with chronic moderate-to-severe low back pain (LBP).     

Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective,randomized, double-blind,placebo- and active-controlled Phase III study

Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain.

Research design: Patients (N = 981) were randomized 1:1:1 to receive tapentadol ER 100 – 250 mg b.i.d., oxycodone HCl controlled release (CR) 20 – 50 mg b.i.d., or placebo over 15 weeks (3-week titration period, 12-week maintenance period).

Main outcome measures: Efficacy was assessed as change from baseline in average pain intensity (11-point NRS) at week 12 of the maintenance period and throughout the maintenance period; last observation carried forward was used to impute missing pain scores. Adverse events (AEs) were monitored throughout the study.

Results: Tapentadol ER significantly reduced average pain intensity versus placebo at week 12 (least squares mean difference vs placebo [95% confidence interval], ?0.8 [?1.22, ?0.47]; p < 0.001) and throughout the maintenance period (?0.7 [?1.06,?0.35]; p < 0.001). Oxycodone CR significantly reduced average pain intensity versus placebo at week 12 (?0.9 [?1.24,?0.49]; p < 0.001) and throughout the maintenance period (?0.8 [?1.16,?0.46]; p < 0.001). Tapentadol ER was associated with a lower incidence of treatment-emergent AEs (TEAEs) than oxycodone CR. Gastrointestinal TEAEs, including constipation, nausea, and vomiting, were among the most commonly reported TEAEs (placebo, 26.3%; tapentadol ER, 43.7%; oxycodone CR, 61.9%). The odds of experiencing constipation or the composite of nausea and/or vomiting were significantly lower with tapentadol ER than with oxycodone CR (both p < 0.001).

Conclusions: Tapentadol ER (100 – 250 mg b.i.d.) effectively relieved moderate to severe chronic low back pain over 15 weeks and had better gastrointestinal tolerability than oxycodone HCl CR (20 – 50 mg b.i.d.).     

Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine

Minor metabolic pathways in human subjects have been shown to exist for the conversion of codeine to hydrocodone but have not been reported for the metabolic conversion of morphine to hydromorphone. In this study, urine specimens were collected in an out-patient setting from 13 pain patients who were chronically treated with morphine and other opioids (methadone, oxycodone, and fentanyl). The chronic pain patients were chosen for study because they were treated with high-dose morphine and had no personal or family history of addiction. Results of the initial evaluation and follow up of these patients with random urine tests did not indicate opioid misuse. The specimens were analyzed by GC-MS for the presence of hydromorphone. The reporting limit for hydromorphone was 100 ng/mL. Ten of the 13 morphine-treated patients excreted hydromorphone in minor amounts ranging 120 to 1400 ng/mL. Concurrent morphine concentrations were exceedingly high in these 10 patients and frequently exceeded the upper limit of linearity (> 10,000 ng/mL) of the assay. The ratio of hydromorphone to morphine ranged from 0.015 to 0.024. Morphine concentrations in the three patients in which hydromorphone was not detected tended to be lower than those observed in other patients. For comparison, one additional patient was included in the study, who was prescribed both morphine and hydromorphone. Concentrations of hydromorphone in this patient were in the range of 3400-13,000 ng/mL, while concurrent morphine concentrations were in the range of 3200-6600 ng/mL. These data are highly suggestive that hydromorphone can be produced as a minor metabolite of morphine in humans. Although additional studies in more restricted settings are needed, it is recommended that interpretation of low urinary concentrations of hydromorphone in combination with high concentrations of morphine in morphine-treated pain patients should not be considered as conclusive evidence of hydromorphone misuse.     

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.     

Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.

Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.

Areas covered in this review: A MEDLINE search was done (January 2002 – July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials.

What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.

Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy – it is a strong analgesic that is well tolerated.     

Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain

ABSTRACT

Objective: Opioid therapy is frequently associated with treatment-limiting constipation. Naloxone is an opioid antagonist with low oral systemic bioavailability. This Phase III clinical trial assessed the safety and efficacy of an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation.

Study design: This double-blind, multicenter trial was conducted in specialist and primary care centers in four European countries in an out-patients setting. The study included 322 adult patients with moderate-to-severe, noncancer pain requiring opioid therapy in a range of ≥20 mg/day and ≤50 mg/day oxycodone. Following a run-in phase patients were randomized to receive oxycodone PR/naloxone PR or oxycodone PR for 12 weeks. The primary outcome was improvement in constipation as measured using the Bowel Function Index (BFI). Secondary/exploratory assessments focused on pain intensity and additional bowel parameters.

Trial registration: NCT00412152.

Results: A significant improvement in BFI scores occurred with oxycodone PR/naloxone PR compared with oxycodone PR after 4 weeks of double-blind treatment (?26.9 vs. ?9.4, respectively; p < 0.0001), observed after only 1 week of treatment and continued until study end. A significant increase in the number of complete spontaneous bowel movements and decrease in laxative use were also reported. This improvement in bowel function was achieved without compromising the analgesic efficacy of the oxycodone component; pain intensity remained constant throughout the study. The incidence of adverse events was comparable in both groups and consistent with those expected of opioid analgesics. As the study was limited to a dose range of up to 50 mg oxycodone equivalent per day, further research on higher doses would be recommended.

Conclusion: The fixed-ratio combination of oxycodone PR/naloxone PR is superior to oxycodone PR alone, offering patients effective analgesia while significantly improving opioid-induced constipation.     

A 12-week,randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT

Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP).

Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10?mg increments every 12?h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12?h for 12 weeks. Oxymorphone immediate release was available every 4–6?h, as needed, for the first 4 days and twice daily thereafter.

Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4?mm at screening to 22.7?mm (?p < 0.0001). After random­ization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (?p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group.

Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12?week double-blind treatment period in opioid-naive patients with CLBP.     

Cost-effectiveness analysis of pregabalin versus gabapentin in the management of neuropathic pain due to diabetic polyneuropathy or post-herpetic neuralgia

ABSTRACT

Objective: To estimate the cost-effectiveness of branded pregabalin (PGB) versus generic gabapentin (GBP) in patients with neuropathic pain (NeP) due to painful diabetic polyneuropathy (DPN) or post-herpetic neuralgia (PHN) in Spain.

Methods: Using stochastic simulation, we estimated the cost-effectiveness of PGB 150–600?mg/d vs. GBP 900–3600?mg/d in a hypothetical cohort of 1000 patients. The model used data from three randomized controlled clinical trials. Pain was evaluated using a 0–10 scale. Mean baseline pain was 6.9 in both treatment groups. The model assigned untreated pain scores over 84 days. Treated scores were calculated using weekly changes in pain scores from trials. Outcomes included the numbers of days with no or mild pain (score < 4), days with ≥ 30% and ≥ 50% reductions in pain intensity, quality-adjusted life-years (QALYs), and estimated health costs.

Results: Compared with GBP, PGB yielded an estimated mean of 8 (standard error, 0.4) additional days with no or mild pain, 6 (0.4) days with ≥ 30% reduction in pain intensity, 9 (0.5) days with ≥ 50% reduction in pain intensity, and a gain of 0.1186 (0.0002) QALYs for 12 weeks. The estimated total health costs of therapies were €1049 (€35) for PGB and €951 (€38) for GBP, respectively. Incremental cost-effectiveness ratio (ICER) for PGB versus GBP were a mean of €12 (95% confidence interval, €1–24) per additional day with no or mild pain, €431 (dominant–€876) per additional patient with no or mild pain, and €20?535 (€1607–40?345) per QALY gained.

Conclusions: According with data used in this modeling in patients with NeP due to DPN and/or PHN, PGB was shown to be more cost-effective than generic gabapentin in Spain.     

An abuse-deterrent,microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia

Background: Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose.

Objective: To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes.

Methods: A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration.

Results: There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size.

Conclusions: Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.     

Management of pain in the elderly at the end of life

Pain is one of the symptoms most frequently encountered in elderly patients at the end of life. The management of pain in the elderly in general has been associated with undertreatment. The geriatric population has been identified as a challenging population with respect to pain management because of issues related to co-morbidities, polypharmacy and cognitive dysfunction. In the geriatric population, the assessment of pain requires measurement of pain intensity, delineation of opioid responsiveness, and clarification of the impact of pain on patients' psychological, social, spiritual and existential domains. Effective pain management is guided by the World Health Organization (WHO) analgesic stepladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength and works effectively in the elderly patient population. Step 1 is reserved for mild pain. Patients in this category are treated with nonopioid analgesics such as acetaminophen, or a nonsteroidal anti-inflammatory, with consideration of an adjuvant analgesic if necessary. Step 2 is reserved for patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but are still experiencing poor analgesic control. Step 2 agents include acetaminophen products containing hydrocodone, oxycodone, codeine and tramadol. Patients with moderate to severe pain require strong analgesics belonging to step 3 of the WHO analgesic stepladder. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone and oxycodone. Familiarity with opioid pharmacokinetics, equianalgesic dosing and adverse effects is necessary for the safe and effective use of these drugs. The appropriate use of adjuvant analgesics such as antiepileptic drugs, antidepressants and local anaesthetics can enhance the use of opioids, especially in cases where opioid responsiveness may be in question, such as with neuropathic pain. This paper will provide an overview of the analgesic considerations for elderly patients at the end of life.     

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol

ABSTRACT

Objective: The purpose of this study was to investigate the pharmacokinetic properties of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) in the presence of alcohol.

Research design and methods: In a single-centre, open-label, four-treatment, four-period, four-sequence, crossover study, two groups of 24 healthy subjects (fasted or fed) were randomised to receive four single doses of OROS hydromorphone 16?mg with solutions of either 0%, 4%, 20% or 40% alcohol, and with a naltrexone block.

Main outcome measures: Plasma samples taken predose and at regular intervals up to 48?h after dosing were assayed for hydromorphone concentrations; a mixed-effect analysis of variance was done on log-transformed data. Bioequivalence was concluded if 90% confidence intervals of treatment mean ratios were between 80% and 125%.

Results: Plasma hydromorphone concentrations were slightly higher after dosing with all alcohol treatments in both the fasted and fed subject groups. Median T_max values were between 12 and 16?h and ranges were similar for all treatments. C_max values increased after alcohol compared with no alcohol, with the increase slightly lower in the fed state. The greatest mean increase in C_max observed was 1.3-fold in the fasted state and 1.1-fold in the fed state. Confidence intervals were within 80–125% for AUC but were slightly higher for C_max.

Conclusions: The pharmacokinetics of once-daily OROS hydromorphone were only minimally affected by alcohol, with no dose dumping of hydromorphone. The results indicate that the controlled-release properties of this formulation are maintained in the presence of alcohol.     

Efficacy and safety of tapentadol prolonged release for moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind,randomized, placebo- and oxycodone controlled release-controlled studies

Objective: To compare efficacy and safety of tapentadol prolonged-release (PR) and oxycodone-controlled release (CR) in moderate-to-severe chronic osteoarthritis knee pain.

Methods: Data from two double-blind, randomized, placebo- and oxycodone CR-controlled phase 3 studies with a 3-week titration period and 12-week controlled dose adjustment maintenance period were pooled. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point).

Results: A total of 2,010 patients were assessed. For both primary end-points, tapentadol PR was significantly more effective than oxycodone CR (LS mean difference of –0.41 [95% CI?=?–0.65, –0.16; p?=?0.001] at week 12 and –0.35 [95% CI?=?–0.58, –0.12; p?=?0.003] over 12 weeks of maintenance [last observation carried forward]). Significantly better outcomes than for oxycodone CR were also observed for patient global impression of change, both Short Form-36 component scores, and EuroQoL-5Dimensions health status index (all p?p?Conclusions: The analyses suggest that tapentadol PR provided superior pain relief and a more improved overall health status than oxycodone CR in a large patient population with moderate-to-severe chronic osteoarthritis pain. Compared to oxycodone CR, tapentadol PR showed a more favorable tolerability profile with better gastrointestinal tolerability.