Modeling the economic and health consequences of managing chronic osteoarthritis pain with opioids in Germany: comparison of extended-release oxycodone and OROS hydromorphone

ABSTRACT

Objective: The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended-release (ER) oxycodone administered two or three times a day.

Methods: This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre-treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros.

Results: Over 1 year on a mean daily morphine-equivalent dose of 90?mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (€141/patient), yielding an incremental cost-effectiveness ratio (ICER) of €8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of €68 per patient, €3979/QALY, and for hydromorphone to 1:7.5 to savings.

Conclusion: Based on these analyses, OROS hydromorphone is expected to yield health benefits at reasonable cost in Germany.     

筋膜释放技术联合核心稳定训练治疗慢性非特异性腰痛的疗效观察

目的 探究筋膜释放技术（MFR）联合核心稳定训练（CSE）治疗慢性非特异性腰痛（CNLBP）的临床疗效。方法 选取2020年10月至2021年7月在山西医科大学第一医院治疗的40例CNLBP病人,采用随机数字表法分为观察组和对照组各20例。两组病人均接受核心稳定训练,观察组在此基础上进行筋膜释放技术治疗,治疗时间为2周。分别于治疗前、治疗1周及治疗2周后对两组病人进行疗效评估,评定方法包括Schober试验、视觉模拟评分（VAS）、Oswestry功能障碍指数（ODI）及恐惧-回避信念问卷（FABQ）。结果 治疗1周后,观察组与对照组Schober试验结果[（3.73±1.16）cm、（2.98±1.14） cm]与治疗前[（3.05±1.27）cm、（2.48±1.02） cm]比较均升高（P<0.001）,观察组与对照组的VAS评分[（2.90±1.28）分、（4.25±1.33）分]、ODI评分[（12.00±4.18）分、（16.45±3.95）分]及FABQ评分[（36.60±11.16）分、（43.80±12.66）分]与治疗前[（4.70±1.13）分、（4.90±...     

穴位皮内针联合腰痛宁胶囊治疗老年慢性腰腿痛的临床疗效观察

目的 探讨穴位皮内针联合腰痛宁胶囊治疗老年慢性腰腿痛的临床疗效。方法 选取 2019年5月至2020年12月于费县人民医院中医科接收的老年慢性腰腿痛患者120例作为研究对象, 采用随机数字表法对半分为对照组与观察组,每组各 60 例。对照组男 28 例、女 32 例,年龄（68.42± 6.09）岁;观察组男 26例、女 34例,年龄（68.05±6.26）岁。对照组在生活指导与运动指导基础上,口服腰痛宁胶囊治疗;观察组在对照组基础上实施穴位皮内针治疗,2周为1个疗程,1个疗程后评价疗效。 比较两组患者的疗效及治疗前后的疼痛数字评分法（NRS）评分、日本骨科协会（JOA）腰椎评分。计数资料组间比较采用 χ2 检验,计量资料组间比较采用独立样本 t 检验,组内采用配对 t 检验。结果 观察组治疗总有效率为91.67%（55/60）,高于对照组76.67%（46/60）,差异有统计学意义（χ2 =5.065,P< 0.05）。两组治疗后腰部、腿部NRS评分均低于治疗前,且观察组治疗后的腰部、腿部NRS评分分别为 （2.95±0.73）分、（3.03±0.78）分,均低于对照组的（3.54±0.92）分、（3.69±0.95）分,差异均有统计学意义 （均P<0.05）。两组患者治疗后JOA腰椎评分中主观症状、临床体征、日常活动受限度及膀胱功能评分均高于治疗前,且观察组治疗后的JOA腰椎评分中主观症状、临床体征、日常活动受限度及膀胱功能评分分别为（6.30±0.65）分、（5.25±1.04）分、（11.08±1.54）分、（-1.02±0.21）分,均高于对照组的（5.63± 0.74）分、（4.76±0.93）分、（9.81±1.61）分、（-1.33±0.28）分,差异均有统计学意义（均P<0.05）。结论 穴位皮内针联合腰痛宁胶囊在老年慢性腰腿痛患者治疗可降低疼痛感,提升腰椎功能,提升治疗有效率。     

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.     

Expert opinion on emerging drugs: chronic low back pain

Introduction: It is difficult to overestimate the personal and socioeconomic impact of chronic low back pain (CLBP). It is the leading cause of years lost to disability and poses the highest economic toll among chronic illnesses. Despite the strong need for extensive research efforts, few drugs have consistently demonstrated effectiveness for this condition.

Areas covered: In this review, the epidemiology, rationale for mechanism-based treatment, competitive environment and market trends, and the preclinical and clinical evidence supporting over 15 different classes of analgesic medications studied for CLBP or related pain conditions are discussed. Treatments are divided by drug category, type of CLBP they are likely to treat (e.g., neuropathic or mechanical), and whether they are new formulations of existing treatments, new indications for existing treatments or represent novel mechanisms of action. Databases searched included MEDLINE, Embase, Pharmaprojects and various clinical trial registries.

Expert opinion: Many barriers exist for the development of medications for CLBP including difficulties in identifying pathophysiological mechanisms, biologic resiliency secondary to multiple concurrent pain pathways and off-target and sometimes serious side effects. Nevertheless, the volume and diversity of novel molecular entities has continued to surge and includes possible disease-modifying therapies such as gene and stem cell therapy.     

针刀治疗慢性下腰痛患者的临床疗效

目的：探讨针刀治疗慢性下腰痛的应用及疗效。方法：将147例慢性下腰痛患者分为两组。治疗组72例,依据关键性治疗点,采用针刀治疗,1次/7 d,3次为1个疗程,共2个疗程。对照组75例采用电针联合特定电磁波谱治疗,1次/2 d,10次为1个疗程,共2个疗程。对两组疗效进行比较。结果：治疗组治疗前与治疗近期和远期（4个月）的VAS差值分别为（4.14＆#177;0.98）分和（3.56＆#177;1.06）分,对照组则分别为（3.12＆#177;1.34）分和（2.47＆#177;1.28）分,组间差异有统计学意义（P〈0.01）。结论：针刀治疗慢性下腰痛有较好的临床疗效,明显优于电针联合特定电磁波谱治疗。     

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.     

针灸联合腰腿痛丸治疗慢性腰腿疼痛综合征的可行性及安全性

目的：探讨针灸联合腰腿痛丸治疗慢性腰腿疼痛综合征的可行性及安全性。方法选取本院2012年10月~2013年11月收入院的慢性腰腿疼痛综合征患者605例,随机分为观察组305例和对照组300例,观察组采用针灸联合腰腿痛丸治疗,对照组采用腰腿痛丸治疗,比较两组的临床疗效、关节疼痛评分及疼痛综合评分。结果观察组总有效率明显高于对照组,差异有统计学意义（P〈0.05）。观察组治疗后的关节疼痛评分明显低于对照组,疼痛综合评分明显高于对照组,差异有统计学意义（P〈0.05）。两组治疗后的关节疼痛评分低于治疗前,差异有统计学意义（P〈0.05）。结论采用针灸联合腰腿痛丸治疗慢性腰腿疼痛综合征,可明显缓解患者疼痛,疗效显著,安全可靠,值得推广应用。     

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.     

Buprenorphine transdermal system and quality of life in opioid-experienced patients with chronic low back pain

Objectives: To evaluate the impact of 12 weeks of treatment with Butrans® (buprenorphine) transdermal system (BTDS) on the health-related quality of life (HRQoL) for patients with chronic low back pain (CLBP), and the maintenance of effects over 52 weeks.

Research design and methods: A multicenter, enriched, double-blind (DB), randomized trial comparing BTDS 20 μg/h (BTDS 20) against 5 μg/h (BTDS 5) for treatment of opioid-experienced patients with moderate-to-severe CLBP, including a 52-week open-label (OL) extension phase.

Main outcome measures: QoL was measured with the SF-36v2 survey before and after an OL run-in period with BTDS 20, three times during the DB phase, and seven times over the extension phase. This post hoc analysis tested for SF-36v2 score differences between treatment groups during the DB phase and maintenance of effects over the extension phase.

Results: At 12 weeks, BTDS 20 produced larger improvements than BTDS 5 in role limitations due to physical health, bodily pain and overall physical QoL (p < 0.01). Treatment group differences in overall physical QoL were sustained throughout the DB phase. Quality-of-life improvements associated with BTDS 20 persisted through the extension phase.

Conclusions: These data suggest that opioid-experienced moderate-to-severe CLBP patients receiving BTDS 20 exhibited better QoL than patients receiving BTDS 5.     

Anti-nerve growth factor antibodies for the treatment of low back pain

ABSTRACT

Introduction

The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects.     

Onset of pain relief with rofecoxib in chronic low back pain: results of two four-week,randomized, placebo-controlled trials

SUMMARY

Objective: We recently reported the efficacy of rofecoxib in two randomized controlled trials in chronic low back pain (CLBP). The objectives of this report are to present data regarding the onset of efficacy of rofecoxib from these trials and propose methods for reporting onset.

Research design and methods: Patients were aged 18-75, with non-radicular CLBP for >3 months. Patients were randomized to rofecoxib 25?mg, 50?mg, or placebo once daily for 4 weeks. Assessments included Low Back Pain and Bothersomeness scales every morning and Relief from Starting Pain after the first dose at 0.5,1, 2, 3,4h, bedtime, and next morning. Onset of meaningful relief was measured by Time to Confirmed 50% Reduction in Pain and Time to Confirmed 'Slightly' or 'Not At All' Bothersome Pain. Onset of perceptible pain relief was measured by Time to At Least 'A Little' Confirmed Pain Relief.

Results: 690 patients entered. Significantly more patients treated with rofecoxib had meaningful relief compared to placebo: 60.4,58.4, and 34.7% for rofecoxib 25mg, 50mg, and placebo (p?<?0.001). Median time to meaningful relief for rofecoxib was 2 days, 1 day sooner than placebo. Rofecoxib was superior to placebo by bedtime after the first dose.

Conclusions: Approximately 2/3 of patients achieved meaningful pain relief with rofecoxib compared with 1/3 receiving placebo. Median time to onset of meaningful relief was about 2 days, but superior relief over placebo was seen by bedtime after the first dose. Onset of perceptible pain relief was within 2?h. We propose that measures of onset of analgesic effect include the proportion of patients who achieve meaningful pain relief and in this subgroup, the time-to-onset of confirmed meaningful reduction in pain intensity, time-to-onset of confirmed pain relief, and time to first separation from placebo in the proportion of patients who achieve meaningful pain relief.     

Treatment for chronic low back pain: the focus should change to multimodal management that reflects the underlying pain mechanisms

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients’ lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians’ knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed.

Diagnosis: Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments.

Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects.

Conclusions: This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and anticonvulsants), supplemented by appropriate non-pharmacological measures such as exercise programs, manual therapies, behavioral therapies, interventional pain management and traction. Surgery may be appropriate in carefully selected patients.     

Efficacy of a new once daily hydromorphone formulation in comparison with twice daily administration in chronic pain: a randomized,double-blind,cross-over study

Objective Efficacy and safety of a novel multiple-unit hydromorphone once daily (HOD) was compared to an established hydromorphone twice daily (HTD) regimen in patients with moderate-to-severe chronic pain.

Design and methods The results from a randomized, double-blind, multicenter, cross-over trial in patients (n?=?37) with chronic malignant or non-malignant pain are reported. The primary efficacy parameter was current pain on 0–100?mm VAS assessed four times daily and prior to intake of rescue medication (immediate-release hydromorphone) throughout the last 5 days with each treatment (after an 8?day build-up period to avoid carry-over effects). Total daily dose of hydromorphone (TDD: 8–32?mg/day) was kept stable during the double-blind treatment phase.

Results The difference observed in mean current pain (?0.92?mm VAS) over the 5?day assessment period between HOD and HTD (28.44?mm vs. 29.36?mm VAS) was found to lack clinical relevance, as the 95% CI (?4.10 to 2.28?mm VAS) did not exceed the prespecified limit for non-inferiority of 9?mm VAS. Results from the full analysis set were consistent with per protocol data confirming robustness, as did the data for 12?h recalled pain assessed at 08:00?h and 20:00?h, showing no significant differences between once and twice daily medication. Both treatments produced effective and stable pain control with only minor day-to-day and intra-day fluctuations. Switching between treatments was suitable, considering both efficacy and safety, as no relevant or significant differences in adverse events were seen (25.0% HOD, 24.3% HTD). Most frequently typical side-effects of opioid therapy were observed, such as nausea, vomiting and headache.

Conclusion Although this study was of short duration and included a limited number of patients, the results confirm that the new HOD is as effective and safe as the established HTD.     

The pharmacological management of chronic lower back pain

ABSTRACT

Introduction

Treating chronic low back pain (LBP) can be challenging, and the most effective pharmacological therapy is controversial. The present systematic review investigated the efficacy of various pharmacological compounds to achieve pain relief and improve disability in chronic LBP patients. The present study focused on acetaminophen, amoxicillin, flupirtine, baclofen, tryciclic antidepressants (TCAs), duloxetine, topiramate, gabapentinoids, non-steroid anti-inflammatory drugs (NSAIDs) and opioids.     

Escitalopram 20 mg versus duloxetine 60 mg for the treatment of chronic low back pain

Background: Escitalopram has never been demonstrated to be useful in the treatment of chronic low back pain (CLBP), while duloxetine has demonstrated analgesic effect in chronic pain states. The aim of this trial was to examine the efficacy of escitalopram for the treatment of CLBP compared with duloxetine. Methods: A total of 85 adult patients with non-radicular CLBP entered a 13-week randomized study comparing escitalopram 20 mg with duloxetine 60 mg once daily. The primary measure was comparison of the two drugs on reduction in weekly mean 24-h average pain. Secondary measures included Clinical Global Impressions of Severity (CGI-S) and the 36-item Short-Form Health Survey (SF-36). Results: Eighty patients (n = 39 escitalopram, n = 41 duloxetine) completed the study. No significant differences existed between escitalopram and duloxetine on reduction in weekly mean 24-h average pain at end point. Both escitalopram and duloxetine demonstrated significant improvement on CGI-S and SF-36. Conclusions: Escitalopram and duloxetine demonstrated efficacy and safety in the management of CLBP, with no significant differences. Results of this study should be replicated in a larger sample of patients.