Pain relief and pain-related sleep disturbance with extended-release tramadol in patients with osteoarthritis

ABSTRACT

Objective: This analysis evaluated changes in pain and pain-related sleep disturbance with extended-release tramadol (tramadol ER) in patients with moderate, chronic osteoarthritis pain, and the influence of pain reduction on pain-related sleep disturbance.

Methods: Data were obtained from a 12?week, randomized, double-blind, placebo-controlled, fixed-dose study of tramadol ER 100?mg, 200?mg, 300?mg, or 400?mg once daily. Subjects reported osteoarthritis pain intensity with a 100?mm visual analog scale (VAS; 0 = no pain, 100 = extreme pain). A Sleep Problems Index score from 0 to 100?mm (0 = never, 100 = always) was determined from the mean of three subject-reported scores of pain-related sleep disturbance.

Results: A total of 815 subjects received tramadol ER (all doses combined) and 205 received placebo. Mean pain reduction at 12 weeks was –30.4?mm and –21.5?mm for tramadol ER and placebo, respectively (?p < 0.001). Tramadol ER-treated subjects were nearly twice as likely as placebo subjects to have clinically meaningful pain reduction at 12 weeks, defined as 30?mm or greater reduction (odds ratio [OR] = 1.84, p < 0.001) or 30% or greater reduction (OR = 1.95, p < 0.001) in pain. Clinically meaningful reduction of pain-related sleep disturbance at 12 weeks, defined as 16?mm or greater improvement on the Sleep Problems Index, was more common for tramadol ER than placebo (51% vs. 42%, respectively, p = 0.022). Pain reduction was associated with reduced pain-related sleep disturbance (R = 0.51). Study treatment was generally well tolerated. Possible limitations included homogeneity of pain scores at baseline and the effect of adverse events on sleep analyses.

Conclusions: In patients with chronic osteoarthritis pain, pain reduction is associated with decreased pain-related sleep disturbance.     

膝骨性关节炎患者膝关节疼痛指数与足底压力变化的相关性研究

目的 探讨膝骨性关节炎患者足底压力改变及疼痛对足底压力的影响。方法 运用足底压力测试系统对28例单侧膝骨性关节炎疼痛患者自然行走时的步态进行测试,观察受试者单足支撑分期时段参数、足角及膝关节疼痛指数,对健、患侧足底压力各指标进行统计学分析并分析膝关节疼痛指数与各指标相关性。结果 膝骨性关节炎患者患侧前足着地阶段时间百分比为(57.90±32.93)、全足支撑阶段时间百分比为(57.93±2.93)低于健侧对应百分比(60.26±2.66,P=0.007; 51.53±3.84, P < 0.001);患侧足角(16.24±4.50)明显高于健侧足角(14.67±4.09),差异有统计学意义(P=0.014);膝关节疼痛指数与患侧前足着地阶段时间百分比(r=-0.53,P=0.004)、全足支撑阶段时间百分比(r=-0.56,P=0.002)呈负相关;与患侧足角无明显相关性(r=0.245,P=0.193)。结论 膝骨性关节炎患者足底压力具有特征性,前足着地时段、全足支撑时段明显缩短、足角变大,疼痛严重影响膝骨性关节炎患者步态。     

Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized,double-blind,placebo-controlled trial

Abstract

Objective:

To determine the efficacy, tolerability, and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis (OA) of the knee with pain of moderate or greater severity.     

Gait analysis and pain response of two rodent models of osteoarthritis

The purpose of this study was to compare the gait parameters recorded on the CatWalk and the mechanical sensitivity with von Frey filaments of two putative models of osteoarthritis over a one month period, and to evaluate the effect of celecoxib on these parameters. Animals underwent either a surgical sectioning of the anterior cruciate ligament with partial medial menisectomy (ACLT + pMMx) to create a joint instability model or received an intra-articular injection of monoiodoacetate (MIA) as a putative inflammatory joint pain model. Animals were assessed for four consecutive weeks and knee joints were then evaluated histologically. Spinal cord lumbar enlargements were harvested for selected neuropeptide analysis (substance P (SP) and calcitonin gene related peptide (CGRP)). With the MIA model, significant changes persisted in selected dynamic gait parameters throughout the study in the injured limb as well as with the von Frey filaments. The ACLT + pMMx model in contrast showed no clear differential response between both hind limb for both gait parameters and pain-related behavior with von Frey filaments occurred only on the last day of the study. Neuropeptide analysis of spinal cord lumbar enlargements revealed a significant increase in CGRP concentration in both models and an increase in SP concentration only in the MIA model. Histological evaluation confirmed the presence of articular cartilage lesions in both models, but they were much more severe in the MIA model. Celecoxib had an effect on all selected gait parameters at the very beginning of the study and had an important alleviating effect on mechanical allodynia. These results suggest that the MIA model may be more appropriate for the evaluation of short term pain studies and that celecoxib may modulate mechanical allodynia through central sensitization mechanisms.     

Recent developments in the treatment of osteoarthritis with NSAIDs

Abstract

Objective:

To conduct a systematic review of evidence supporting the efficacy and safety profiles of nonsteroidal anti-inflammatory drugs (NSAIDs) introduced in the last decade for the treatment of patients with osteoarthritis (OA), including their analgesic effects, ability to improve function, and adverse event profiles relative to current standards of care.     

Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis

SUMMARY

Recent literature and animal research has provided insight to potentially new analgesic targets for managing osteoarthritis (OA) pain. Primary afferent neurons located in affected joints express excessive amounts of abnormally functioning sodium (Na) channels on their surface in response to the inflammatory process. These Na channels may play an integral role in production of pain and hyperalgesia. Hence, the authors set out to conduct a 2-week, open-label, multicenter proof-of-concept study to evaluate the effectiveness and safety of lidocaine patch 5% monotherapy in adults with OA pain of the knee (?n = 20). Patients with OA of one or both knees who were experiencing inadequate pain relief (defined as an average daily pain intensity of > 4 on a 0 to 10 pain scale) with their current analgesic regimen (i.e. APAP, NSAIDs, COX-2 inhibitors, tramadol) were enrolled and had all analgesic medications discontinued. Treatment with the lidocaine patch 5% resulted in significant improvements in the Western Ontario and McMaster Universities OA Index (WOMAC) pain, stiffness, physical function subscales and composite index (48.4, 41.1, 47.0, and 46.8% improvements respectively, p < 0.01). In addition, significant improvement was noted for pain intensity, pain relief, and pain interference with quality of life as measured by the Brief Pain Inventory (?p < 0.05). The lidocaine patch 5% was generally well tolerated and no patients discontinued due to treatment-related adverse events. Given the open-label design, lack of a control group, and small sample size, the findings from our pilot study need to be confirmed by larger randomized controlled trials. Topical lidocaine patch 5% may provide clinicians with a novel, non-systemic therapy for OA pain with a unique mechanism of action.     

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.     

Benefits of transdermal fentanyl in patients with rheumatoid arthritis or with osteoarthritis of the knee or hip: an open-label study to assess pain control

SUMMARY

Objectives: To evaluate the effectiveness and safety of transdermal fentanyl (TDF) for the treatment of pain associated with rheumatoid arthritis (RA) or osteoarthritis of the knee or hip (OA), which was not adequately controlled by non-opioid analgesics and/or weak opioids.

Methods: The study design incorporated a 1-week run-in period when current analgesic medications were optimised, a 28-day treatment period and a 1-week taper-off period. Patients with RA (n = 104) and OA (n = 159) started treatment with TDF 25?µg/h. Patches were replaced every 72?h, with the option to up-titrate until adequate pain control was achieved. Metoclopramide was taken during the first treatment week and as needed thereafter.

Results: 203 patients completed the treatment phase, 90 entered the taper-off phase. 25?µg/h was the most frequently used maximum dose (51%). Pain control was increased from 4% to 29% of patients during run-in. The number of patients reaching adequate pain control in the first treatment week was increased to 75%, and increased further to 88% on day 28 and to 80% at endpoint. From baseline (screening) to endpoint, there were significant reductions in pain (?p < 0.001) on the Wisconsin Brief Pain Inventory, and significant improvements in quality of life (Short-Form-36: physical p < 0.001; mental health p < 0.05). Eighty per cent of the patients (n = 134) assessed the treatment favourably; nausea and vomiting were the most common adverse events, mainly occurring at treatment initiation. Efficacy of metoclopramide appeared limited. TDF could be initiated in patients pre-treated with non-opioid analgesics or weak opioids and tapered off without major complications.

Conclusions: TDF significantly improved pain control and quality of life, and was well tolerated in patients with RA or knee/hip OA who continued to experience pain on their current analgesic treatment. Treatment could be discontinued without issues. Nausea and vomiting was usually mild during treatment initiation. Patients’ well being could be further accommodated by optimising prophylactic treatment.     

Utilization of duloxetine and celecoxib in osteoarthritis patients

Abstract

Objectives:

To describe utilization patterns of duloxetine and celecoxib and subsequent opioid use among patients with osteoarthritis.     

Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol

Both the analgesic drugs tramadol and paracetamol are widely used for the symptomatic therapy of osteoarthritis (OA). The aim of this double-blind, randomised study in patients with knee OA was to compare their effects on synovial fluid concentrations of interleukin (IL)-6 and substance P (SP). Moreover, we evaluated plasma and synovial fluid concentrations of tramadol and its active metabolite (O-desmethyl-tramadol, M1) after oral treatment with this drug. Twenty patients were enrolled. A group of 10 patients received tramadol (50 mg three times a day), and another group of 10 patients were treated with paracetamol (500 mg three times a day) for 7 days. Both drugs significantly reduced the intensity of joint pain. The synovial fluid concentrations of SP were significantly reduced only by the treatment with tramadol. In this group of patients, IL-6 synovial fluid concentrations were slightly, but not significantly, decreased. Paracetamol did not significantly change the synovial fluid concentrations of SP and IL-6. After oral administration, a considerable amount of tramadol was measurable in synovial fluid. Both in plasma and synovial fluid the concentrations of M1 were markedly lower than those of tramadol, with a T/M1 ratio of 14.7+/-4.6 and 9.3+/-3.9, respectively. These data demonstrate that the activity of tramadol may involve the modulation of inflammatory mediators. Moreover, they indicate that after oral treatment with tramadol, both the parent drug and its active metabolite can penetrate into synovial fluid.     

中医康复治疗老年骨性关节炎80例效果观察

目的研究中医综合康复疗法在老年骨性关节炎诊治中的治疗效果及安全性。方法随机选取该科2013年2月至2014年1月诊治的80例老年骨性关节炎患者,根据治疗方案分为中医组与西医组,各40例。中医组患者均接受中医康复治疗,主要包括手法推拿、中药熏洗、中药内服（包括六味地黄丸及自制当归四逆汤）,疗程3周。西医组患者采用西药治疗,给予关节内注射25 mg玻璃酸钠,每周1次;口服0.75 g盐酸氨基葡萄糖胶囊,每天2次,均连续治疗3周。通过对照分析两组治疗方案的临床疗效及视觉模拟评分表（JOA）、视觉模拟评分表（VAS）评分。结果中医组显效率[62.5%（25/40）]、总有效率[92.5%（37/40）]明显高于西医组[25.0%（10/40）、65.0%（26/40）],差异均有统计学意义（P〈0.05）;治疗前,中医组JOA、VAS评分[（50.2±10.6）、（7.8±2.3）分]与西医组[（49.9±11.2）、（7.7±2.4）分]比较,差异均无统计学意义（P〉0.05）;治疗后,两组患者JOA评分[（91.5±16.3）、（84.1±13.3）分]较治疗前明显升高,VAS评分[（2.4±1.2）、（3.6±1.8）分]较治疗前明显降低,且中医组JOA、VAS评分明显优于西医组,差异均有统计学意义（P〈0.05）。结论中医康复疗法对老年骨性关节炎不仅具有良好的治疗效果,同时不良反应小、安全可靠,可在临床推广应用。     

Acute back pain: benefits and risks of current treatments

Abstract

Objective:

To review the efficacy and safety of current treatments for acute low back pain.     

An open-label study of a second course of hylan G-F 20 for the treatment of pain associated with knee osteoarthritis

SUMMARY

Objective: To evaluate the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain in patients who experienced a clinical benefit with an initial course of therapy.

Research design and methods: In this prospective, open-label study, men or women (≥40 years of age) with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. Consecutive patients who requested a second course of hylan G-F 20 therapy due to OA knee pain subsequent to pain relief with a first course of therapy were enrolled between October 26, 2000 and January 18, 2001.

Main outcome measures: Pain while walking on a flat surface (Western Ontario and McMaster's Universities Osteoarthritis Index, WOMAC, question A1), WOMAC domain C (physical functioning), full WOMAC, and patient and investigator overall visual analog scales (VAS). Efficacy variables were measured at baseline and at weeks 1,2,4,8,12 and 26. An analgesic washout was required before all efficacy evaluations.

Results: Patients receiving at least one injection of hylan G-F 20 (n?=?71) were predominantly Caucasian (84.5%) and female (64.8%), with a mean age of 65.5 years and mean weight of 200.1 pounds. The mean time between the first and second courses of hylan G-F 20 was 19.6 months (median 17.6 months). With hylan G-F 20, pain while walking on a flat surface was significantly lower (p?<?0.001) than baseline at all time points up to week 26 (mean?±?SEM: ?1.40?±?0.10 at week 26). Actual scores decreased from 2.4?±?0.10 at baseline to 0.97?±?0.11 at week 26. Scores for the WOMAC domain C, full WOMAC and patient and investigator overall VAS also significantly improved (p?<?0.001) at all time points. A second course of hylan G-F 20 was generally well-tolerated, based on the low incidence of local adverse events (AEs) -only one patient (1.4%) experienced a severe event, the types of AEs, and the fact that no patients discontinued the study due to these AEs. The types of related AEs observed were not qualitatively different from those listed in the current product information and published literature.

Conclusion: A second course of hylan G-F 20 therapy is an appropriate therapy for the treatment of OA knee pain in patients who had a previous favorable clinical response. For continued relief of osteoarthritis knee pain, this study supports repeat use of hylan G-F 20 in these patients.     

Open-label study of the safety and effectiveness of long-term therapy with extended-release tramadol in the management of chronic nonmalignant pain

ABSTRACT

Background: Tramadol ER is a once-daily oral analgesic for management of moderate-to-moderately severe chronic pain in adults who require around-the-clock treatment of pain. This study evaluated long-term safety of tramadol ER and effectiveness outcomes in the management of chronic, nonmalignant pain.

Methods: Patients enrolled directly for approximately 1 year of open-label tramadol ER treatment if they had chronic, nonmalignant pain (n = 919), or ‘rolled over’ for 38 weeks of open-label tramadol ER treatment if they completed either of two 12-week, placebo-controlled studies of tramadol ER for low back pain (n = 72) or osteoarthritis (n = 61). Tramadol ER was titrated to a dose of 300?mg once daily (patients ≥?75 years) or 300–400?mg once daily (patients <?75 years).

Results: A total of 257 (24%) patients completed the study. Common adverse events, regardless of treatment relationship, were nausea, dizziness (excluding vertigo), and constipation. Mean scores for current pain intensity (from 0 = no pain to 100 = extreme pain) and least, worst, and average pain intensity over the past week improved at every post-baseline visit. At each post-baseline visit, >?50% of patients provided a global assessment rating of good, very good, or excellent. Study limitations were mandatory titration to 400?mg in some patients, concomitant analgesic therapy as a confounding variable, and lack of a placebo comparator.

Conclusions: Individualized dose titration and limiting once-daily therapy with tramadol ER to the maximum recommended daily dose of 300?mg may balance tolerability and analgesic effects of tramadol ER in patients with chronic, nonmalignant pain.     

Complexities in the pharmacologic management of osteoarthritis pain

Abstract

Objective:

To discuss challenges in the pharmacologic management of osteoarthritis (OA) pain.     

Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: implications for preclinical behavioral assessment of chronic pain

Pain stimulates some behaviors (e.g., withdrawal responses) and depresses other behaviors (e.g., feeding and locomotion). We are developing methods for testing candidate analgesics using measurements of pain-depressed behaviors. Such assays may model important aspects of clinical pain and complement traditional procedures that measure pain-stimulated behaviors. The present study characterized the effects of a chronic pain manipulation (monosodium iodoacetate (MIA)-induced osteoarthritis) on wheel running in rats. Rats had 24 h voluntary access to running wheels. Duration of running wheel acquisition was manipulated such that rats had either 21 or 7 days of running wheel access prior to MIA administration. Wheel running was monitored for an additional 21 days following MIA administration. MIA produced concentration- and acquisition length-dependent decreases in wheel running. Parallel experiments demonstrated that MIA produced concentration-dependent tactile allodynia and shifts in hind limb weight bearing. MIA was differentially potent across assays with a potency rank: weight-bearing ≥ von Frey > running wheel. MIA produced greater depression of wheel running in rats with relatively high baseline running rates compared to rats with relatively low baseline running rates. The differential potency of MIA across assays and apparent rate-dependent effects in running wheels may impact our traditional interpretations of preclinical nociceptive and antinociceptive testing.     

盐酸曲马多缓释片治疗晚期癌症疼痛的评估与护理分析

目的对采用盐酸曲马多缓释片对癌症晚期患者的疼痛症状进行控制的效果和相关护理措施进行分析。方法抽取在过去一段时间内来本院就诊的94例癌症晚期的临床确诊患者病例,将其随机分为A、B两组,每组47例。A组患者采用临床常规镇痛药物进行治疗;B组患者采用盐酸曲马多缓释片进行治疗。对两组患者的疼痛控制情况、并发症和不良反应现象进行比较分析,并总结相应的护理体会。结果经过仔细研究后笔者发现,用药后B组患者的疼痛程度明显轻于A组患者,且差异有统计学意义(P<0.05);两组患者在治疗的过程中,均未出现由止痛药物引起的并发症和不良反应现象,差异无统计学意义(P>0.05)。结论采用盐酸曲马多缓释片对癌症晚期患者进行镇痛治疗,可以使患者的疼痛感得到有效控制,痛苦明显减轻,而无特殊并发症和不良反应现象。