to improve with continued use and often resolve completely, OIC does not get better with repeated administration. Laxatives are commonly used, but their effects do not specifically affect the cause of constipation. By contrast, drugs with a specific mechanism, such as antagonism with intestinal opioid receptors, may provide a therapeutic effect with a reduce impact of OIC. Targeted therapies, with a combination of opioids with an opioid antagonist focusing on the specific mechanism of OIC may reduce gastrointestinal adverse effects, while maintaining systemic analgesia. The aim of therapy with PR OXN is to offer analgesic therapy with an opioid compound like OX while providing a prevention of constipation, which is one of the most frequent opioid-related adverse effect, through the association with N. PR OXN represents a recent and widely used therapy, approved for the treatment of severe pain which can be adequately managed only with opioids.
The 45-day treatment with low-dose OXN-PR was well tolerated by the elderly patients of the present study, affected on average by multiple comorbidities. In addition, our patients were all naïve to strong opioids (a requirement for inclusion in the analysis), most of them (89%) were naïve to any opioid, and more than 40% were not receiving any analgesic therapy at baseline. Despite these character- istics, the switch to OXN-PR, or its initiation, was easy to perform and well tolerated. This is noteworthy especially considering that the fear of opioid-related AEs, including respiratory depression, functional and cognitive impair- ment, and development of drug dependence, is one of, and perhaps, the major reason for the persistent reluctance to prescribe strong opioids to older individuals. Clearly, long-term studies are necessary for a thorough evalua- tion of OXN-PR safety in chronicpainmanagement. The reported AEs in the present study, the majority of which were already present at baseline and may have been related to previous treatments, were all of mild intensity and did not require any treatment or change in OXN-PR dose. This may be a consequence of the low OXN-PR dosages used. Notably, the frequency of nausea/vomiting, a common opioid-related side effect, was low. A possible explana- tion is that the combination of oxycodone with the opioid antagonist naloxone improves not only constipation but also other opioid-related gastrointestinal effects, as suggested by other authors. 37
In Japan, strong opioids that are indicated for CNCP are currently limited to morphine (oral rapid-release for- mulation and injection) and fentanyl patches. 7 The Narcotics and Psychotropics Control Act of Japan stipu- lates that most opioids, designated as narcotics, must be prescribed solely by doctors with opioid prescription license and that records for the transfer of opioids should be maintained throughout the entire distribution process, 11 thereby ensuring that the opioid management system is more tightly regulated than in Western countries. Moreover, evidence suggests that physicians in Japan are more cautious about the use of medical narcotics and less enthusiastic about prescribing them compared to those in the US. 12 This is likely the reason for the extremely low rate of overdose-related admissions reported in Japan from October 2012 through September 2013 13 compared with overdose-related emergency admissions in the US. 14 However, strict control and avoidance of opioid use could potentially limit options for management of patients with chronicpain in Japan.
Background: Two-thirds of older people suffer from chronicpain and finding valid treatment options is essential. In this 1-yearlong investigation, we evaluated the efficacy and safety of prolonged-releaseoxycodone–naloxone (OXN-PR) in patients aged $70 (mean 81.7) years. Methods: In this open-label prospective study, patients with moderate-to-severe noncancer chronicpain were prescribed OXN-PR for 1 year. The primary endpoint was the proportion of patients who achieved $30% reduction in pain intensity after 52 weeks of treatment, without worsening bowel function. The scheduled visits were at baseline (T0), after 4 weeks (T4), and after 52 weeks (T52).
The final to basal pain intensity difference and the positive response rate provided different information on the analgesic effect. In clinical studies, the results are mainly driven by the whole population’s mean values for specified outcomes and end points. The former method offers a general picture of the efficacy of a given treatment but does not allow to dis- tinguish good from bad responses. A poor analgesic effect is a primary issue in clinical practice and a lack of response is Table 1 Main baseline demographic and clinical characteristics of
Background: Strong opioids, including oxycodone, are the most effective analgesics used to combat moderate to severe cancer pain, but opioid-induced bowel dysfunction is a relevant problem associated with the therapy. Clinical studies have demonstrated equivalent analgesic efficacy and improved bowel function in treatment with a fixed combination of prolonged-release (PR) oxycodone and PR naloxone compared to oxycodone alone in patients with nonmalignant pain. Here, we report of a prospective, non-interventional study evaluating the effectiveness and safety of PR oxycodone/PR naloxone in a subgroup of patients with severe cancer pain. Patients and methods: Within the non-interventional multicenter study, 1,178 cancer patients with severe chronicpain received PR oxycodone/PR naloxone, dosed according to pain intensity, for 4 weeks. Recorded variables included pain intensity, patient-reported bowel function (Bowel Function Index), and pain-related functional impairment as a measure of quality of life (QoL).
The results of this analysis in patients aged $75 years, one- fifth of whom were older than 85 years, indicate that the fixed combination of strong opioid agonist–antagonist at low dose can be used effectively and safely for the treatment of chronic moderate to severe pain in subjects who have never been treated before with opioid analgesics. According to our findings, the switch from a non-opioid analgesic regimen to a strong opioid was successful even in patients at high risk of discontinuing opioid treatment early, due to potential opioid- induced worsening of the bowel dysfunction already present at baseline. Indeed, none of the patients discontinued treat- ment due to constipation. Among our patients with severe pain and bowel dysfunction, .60% responded to low-dose OXN-PR with a rapid and clinically relevant relief of pain and improvement, or no worsening, of constipation despite a reduction in the use of laxatives. Such clinical improve- ment was relevant for the patients, as highlighted by the high proportions of those who perceived themselves much or extremely improved. The treatment was well tolerated, with ,2% of patients discontinuing treatment due to severe AEs (somnolence, confusion, visual disturbances).
The OXN2001 trial (ClinicalTrials.gov identiﬁer NCT00513656) 32 was a 4-week, international, multicen- tre, randomized, double-blind, active-controlled, double-dummy, parallel-group, Phase II study, designed to evaluate the safety and eﬃcacy of OXN PR in patients with moderate/severe chronic cancer pain. The study was initiated on 2 November 2007 and the extension phase was completed on 17 August 2010. Following the screening period (3–10 days before randomization), eligible patients stopped their pre- study opioid and laxative medication and were ran- domized (on Day 1/Visit 2) to switch directly to either OXN PR or OxyPR during the 4-week double-blind treatment phase. During the core phase of the study, all subjects, investigators and sponsor personnel were blinded. Treatments were masked in a double-dummy fashion, whereby subjects randomized to receive OXN PR were given OXN PR and OxyPR placebo, and sub- jects randomized to receive OxyPR were given OxyPR and OXN PR placebo. Patients attended three further clinic visits (on Days 8, 15 and 29), and received four additional telephone calls (on Days 2, 4, 6 and 22). Patients could enter an open-label extension phase, the details and results of which will be reported sepa- rately. The study was performed in full compliance with applicable Good Clinical Practice 33 and regulations, and in accordance with the Declaration of Helsinki. 34
From a pharmacological point of view tapentadol PR (prolongedrelease – commercial name: Palexia®, Grunenthal Srl, Italy) is the first of a new class of drugs, namely MOR-NRI: a novel analgesic with a dual mech- anism of action, featuring a μ opioid receptor agonist (MOR) and a noradrenaline reuptake inhibitor (NRI). This single molecule thus combines the analgesic actions of both mechanisms in a synergistic fashion, while eliciting a minimal serotonergic effect (Tzschentke et al., 2014; Langford, 2016; Coluzzi & Ruggeri, 2014). Taken separately, the analgesic effects of each mechanism are quite modest, yet together they are able to produce a greater effect comparable to that of a more traditional, single mechanism opioid such as morphine or oxy- codone (Schroder et al., 2011). Conversely such a syner- gistic effect does not elicit more profound or more frequent collateral effects (nausea, vomit, constipation) (Langford, 2016; Cowan et al., 2014; Afilalo et al., 2010). Moreover, differently from any other product, it does not require CYP enzyme activation and does not inter- fere with hematic clotting functions. These features therefore avoid surgery-associated risks and the need to suspend painmanagement treatment (as is seen with the use of FANS) (Tzschentke et al., 2014; Langford, 2016; Pergolizzi et al., 2016; Sanchez de Aguila et al., 2015). Additionally, since it does not depend on enzymatic acti- vation, use of the molecule reduces the effect of patient variability in painmanagement, as is observed with the
In addition to pain relief, pain control is fundamental to optimize wound care. Treatment adherence is, in effect, increased, and the compliance to change of wound dressings ameliorated as well. In our two cases, the treatment with oral OXN-PR allowed a better local management of DUs, especially in the tolerability of deep wound surgical deb- ridement that otherwise was very difficult to carry out without adequate procedural painmanagement. Moreover, SSc-related calcinosis is often associated with painful DUs as a worsening factor. 20 In both cases, calcinosis was present;
A bespoke online clinician audit tool was developed to support pain centers in collecting patient data and evaluat- ing clinical outcomes of patients taking PR OXN. It was developed with input from a steering group of pain experts from the UK and Ireland with expertise in the management of chronicpain. Between November 2013 and January 2015, this audit tool was used in a study conducted in 13 centers in the UK and Ireland. Participating centers were located across the spectrum of patient care in primary care (Ireland) and secondary care (UK). Patients were prescribed PR OXN after continuing to experience OIC despite the use of laxatives with their previous opioid or if they were unable to tolerate laxatives due to their side effects. The decision to prescribe PR OXN was entirely at the investigator’s discretion, and was not based on any strict inclusion or exclusion criteria. The aim of the study was to assess the efficacy of PR OXN in terms of improvements in constipation and QoL.
Patients were eligible for inclusion in the study if they met the following criteria: diagnosis of solid tumor, the presence of moderate-to-severe pain at baseline defined as average pain intensity (API) score 4 measured on a 0–10 numerical rating scale and requiring around-the-clock WHO step III opioids (strong opioids), no previous treatment with around-the-clock opioids (ie, opioid naïve), and suitable for treatment with a new prescription of prolonged-release OXY or OXN. Pregnant women, patients with a history of alcohol and/or drug abuse or cognitive impairment, and those treated with chemo- and/or radiotherapy in the 15 days before or during the observation period were excluded.
Abstract Pain is a relevant and often underestimated non-motor symptom affecting the quality of life of patients with Parkinson’s disease (PD). Although some pain symptoms can be effectively treated by dopaminergic medication, a correct diagnosis of the different types and distribution of pain in PD is challenging, and accordingly, its treatment remains troublesome. We evaluated the effi- cacy and the safety of a prolongedreleaseoral formulation of oxycodone hydrochloride combined with naloxone hydrochloride dehydrate, in a fixed ratio of 2:1 (OXN PR). A total of 16 PD patients with history of pain with a minimum intensity of four on numerical rating scale (NRS) received low-dose OXN PR (5/2.5 mg twice daily) and were observed for a period of 8 weeks. The primary effi- cacy measure was the pain severity measured with NRS and Brief Pain Inventory (BPI). Secondary efficacy mea- sured the safety profile by recording the occurrence of side effects, clinical global impression of change (CGI-C), Parkinson’s disease sleep scale 2 (PDSS-2), Bowel func- tion index (BFI). Data were collected and analyzed using descriptive statistics. Patients who completed the study (14 out of 16) reported a significant pain relief as observed by the reduction of NRS and BPI scores. No adjustment of dopaminergic therapy was required. No significant changes were observed in bowel function and constipation symp- toms as measured by the BFI during the 8-week period.
The findings of this prospective study involving older patients suffering from chronicpain of moderate-to-severe intensity suggest that low doses of OXN-PR provided effective anal- gesia and were generally well tolerated with no occurrence of constipation and other opioid-related complications. The ben- efits of the treatment also included significant improvements in quality of life and functional state. While this is not a double-blind, randomized, controlled clinical trial, the data suggest that low-dose oral OXN-PR appears to be a valid treatment option for persistent moderate-to-severe pain in geriatric patients with an insufficient response to paracetamol and/or NSAIDs or weak opioids. Our findings provide useful guidance for future studies to confirm the appropriate use of OXN-PR in the management of old and very old (80 years) patients suffering from chronicpain.
Opioids are routinely used in the treatment of moderate- to-severe pain in a wide range of conditions. Despite their analgesic efficacy, chronicmanagement with opioids is often compromised by adverse effects which include nausea, sedation, euphoria/dysphoria, itching, and what is called OIBD. OIBD comprises several gastrointestinal AEs including constipation that can significantly reduce quality of life. Laxatives are the most commonly used treatments for OIBD, although they are not very effective, since they are not mechanism based. Naloxone is an opioid receptor antagonist with low systemic bioavailability (,3%). If administered orally, naloxone antagonizes the opioid recep- tors in the gut wall, while its extensive first-pass hepatic metabolism ensures the lack of antagonist influence on the central opioids receptor. Naloxone does not appear to impair
term benefit is assessed in comparative studies of dopamin- ergic drugs. A further step to optimize indications of RLS management with opioids will be the individuation of poten- tially responder patients, possibly based on the characteriza- tion of specific RLS phenotypes. Given the clinical relevance of sensory symptoms, we think that the design of future trials should also include outcome measures mutuated from pain medicine, 13 as the sensory profile could represent a predictive
Abstract: This open-label, phase 3b study (ClinicalTrials.gov Identifier: NCT00983073) evaluated the effectiveness, and tolerability of tapentadol for severe, chronic osteoarthritis knee pain that was inadequately managed with World Health Organization (WHO) Step I or II analgesics or co-analgesics, or that was not treated with regular analgesics. Prior to starting study treatment, patients discontinued any WHO Step II analgesics, while Step I analgesics and/or co-analgesics were continued at the same dose. Patients received tapentadol prolongedrelease (50–250 mg bid) during a 5-week titration period and a 7-week maintenance period. Doses of tapentadol immediate release 50 mg (#twice/day; $4 hours apart) were permitted throughout the study (total daily dose of tapentadol prolonged and immediate release, #250 mg bid). The primary endpoint was the change in pain intensity on an 11-point numerical rating scale-3 (NRS-3; recalled average pain intensity [11-point NRS] during the last 3 days) from baseline to Week 6, using the last observation carried forward (LOCF) to impute missing pain intensity scores. The mean (standard deviation) change from baseline to Week 6 (LOCF) in pain intensity was −3.4 (2.10; P , 0.0001) for all patients evaluated for effectiveness (n = 195). Significant decreases in pain intensity were also observed at Weeks 6, 8, and 12 (all P , 0.0001) using observed-case analysis. Corresponding significant improvements from baseline to Weeks 6 and 12 were observed in the Western Ontario and McMaster Universities osteoarthritis index, the EuroQol-5 Dimension health status questionnaire, the Short Form-36 health survey, and the Hospital Anxiety and Depression Scale (all P # 0.0103). Treatment-emergent adverse events were in line with those observed in previous studies of tapentadol prolongedrelease. Overall, the results of this study indicate that tapentadol treatment results in significant improvements in pain intensity, health-related quality of life, and function in patients with inadequately managed, severe, chronic osteoarthritis knee pain.
Abstract: Osteoarthritis (OA) is a physically and emotionally debilitating disease that predominantly affects the aging adult population. Current pharmacologic treatment options primarily consist of nonsteroidal anti-inflammatory drugs and/or acetaminophen, but associated side effects, analgesic limitations, especially in the elderly, and the need for around-the-clock analgesia have led physicians to search for alternative analgesics. Opioids have shown effectiveness at mitigating both chronic cancer and noncancer pain, and their ability to be placed into controlled release (CR) formulations suggests that they may prove efficacious for OA patients. One formulation, oxycodone CR, has shown effectiveness in cancer pain patients and in some trials of noncancer low back pain. In this review, the objective was to synthesize the reported findings by researchers in this field and present an up-to-date look at the efficacy, safety, and tolerability of oxycodone CR in OA patients. Public literature databases were searched using specific keywords (eg, oxycodone CR) for studies assessing the efficacy and safety profile of oxycodone CR and its use in patients with OA. A total of eleven articles that matched the criteria were identified, which included three placebo-controlled trials, six comparative trials, one pharmacokinetic study in the elderly, and one long-term safety trial. Analysis of the studies revealed that oxycodone CR is reasonably efficacious, safe, and tolerable when used to manage moderate to severe chronic OA pain, with similar side effects to that of other opioids. Keywords: oxycodone, extended release, controlled release, opioid, osteoarthritis
36.1±10.9 (33.5–38.8) 40.8±12.2 (38.1–43.6) Notes: Data are mean ± standard deviation (95% confidence interval) or number of patients (%). SF-12 German population norms are 49.6 for the average physical sum score and 52.3 for the average mental sum score. haDs: sum score 1−7= normal, 8−10= mildly affected, 11−21= moderately to severely affected. MFhW: 0= worst possible state to 5= best possible state; , 2.5= abnormal. mPDi: from 0= no impairment to 10= total impairment. QliP: sum score from 0= most affected to 40= not affected; # 20= severely affected. Abbreviations: LOCF, last observation carried forward; HADS, Hospital Anxiety and Depression Scale; MFHW, Marburger Fragebogen zum habituellen Wohlbefinden [Marburg questionnaire on habitual health findings]; mPDI, modified Pain Disability Index; QLIP, Quality of Life Impairment by Pain inventory; SF, short form.