Tapentadol Prolonged Release for Severe Chronic Osteoarthritis Pain in the Elderly-A Subgroup Analysis of Routine Clinical Practice Data.

Background Tapentadol prolonged release (PR) has been shown effective and generally well tolerated in a broad range of chronic pain conditions. This subgroup analysis investigated its benefits for elderly patients with severe chronic osteoarthritis (OA) pain in routine clinical practice. Patients and Methods. Data of all patients with chronic OA pain were extracted from the database of a prospective, 3-month noninterventional tapentadol PR trial. The data of elderly OA patients (>65 years of age; n = 752) were compared with the data of younger OA patients (≤65 years; n = 282). Results Almost all patients (elderly 98.7% and younger patients 99.3%) had received long-term analgesic medication prior to the start of tapentadol PR treatment but presented with severe pain accompanied by considerable impairments in sleep quality and quality of life measures. Tapentadol PR provided effective pain relief in both patient groups, with slightly better outcomes in younger patients. However, the mean baseline pain intensity of 7.1 (SD 1.5) was reduced by 3.8 points (p ≤ 0.001), and sleep and quality of life measures had also markedly improved in the elderly: quality of sleep by 3 points, quality of life by 3.4 points, social activities by 3 points, and independence by 2.7 points (p ≤ 0.001 for all measures; 11-point scale). At the end of observation, 68% of the elderly had clinically relevant pain reductions of at least 50% (vs baseline), and 87.9% attained either their intended pain reduction target and/or an additional individual treatment target (both predefined during baseline examination). Only 8.4% of the elderly experienced adverse drug reactions, most frequently nausea (2.7% of patients) and dizziness (1.5%). Conclusion Tapentadol PR provided effective and well-tolerated treatment of severe chronic OA pain for elderly patients in routine clinical practice. The favorable tolerability profile in particular suggests tapentadol PR as a treatment option before classical strong opioids are considered.


Introduction
Chronic pain is a common healthcare problem in the general adult population of the European Union and incurs high total population costs [1]. Many chronic pain patients are elderly, and this number is increasing in view of the aging population. Pain treatment is challenging in this age group; pain is often multifactorial and can be more difficult to assess, in particular, when communication and cognitive capacities decline [2]. Furthermore, multiple comorbidities can make the treatment of pain complex.
Tapentadol prolonged release (PR) has been shown to be effective and generally well tolerated in a broad range of chronic pain conditions [3]; trial data of up to 2 years of treatment also indicate good long-term safety and efficacy [4]. An analysis of routine clinical practice data since the introduction of tapentadol confirms the favorable overall safety profile of the medication [5]. In the management of moderate to severe chronic painful osteoarthritis (OA), one of the leading causes of disability in the elderly [6], tapentadol PR provided beneficial effects in several clinical trials [4,[7][8][9][10][11][12][13] including trials and subgroup analyses in the elderly [11][12][13]. e comparison to oxycodone controlled release (CR) suggested better pain relief and a more improved overall health status under tapentadol PR treatment [14]. e tolerability profile, in particular regarding gastrointestinal side effects, was also more favorable [12][13][14]. e latter is thought to be a consequence of a reduced μ-opioid load [15] due to the combination of two synergistic mechanisms of action (μ-opioid receptor agonism and noradrenaline reuptake inhibition) within the tapentadol molecule [16]. To investigate the administration of tapentadol PR in elderly patients under real-world clinical management conditions, we extracted the data of all patients with chronic OA pain from the database of a noninterventional tapentadol PR trial [17] and compared the data of elderly OA patients (>65 years of age) with the data of younger OA patients (≤65 years).

Patients and Methods
e presented data were extracted from the database of a prospective, noninterventional trial conducted between October 2010 and June 2011 in routine clinical practice (general practitioners and internists) in accordance with Section 4, Subsection 23, sentence 3 and Section 67, Subsection 6 of the Medicinal Products Act of the Federal Republic of Germany [17]. As required by law, the German Federal Institute for Drugs and Medical Devices, the German Association of Statutory Health Insurance Physicians, and the German Federal Associations of Health Insurance Funds were notified of the trial. e trial investigated the routine administration of tapentadol PR in clinical practice. Adult patients with severe chronic pain, who-in the opinion of the treating physician-were indicated for tapentadol PR treatment, could be enrolled. All treatment decisions were solely at the discretion of the treating physician. Tapentadol PR was prescribed in accordance with the summary of product characteristics current at the time [18] depending on previous treatment and pain severity. Adjustment of initial tapentadol PR doses within 3 days was recommended in case of insufficient analgesia (maximum recommended daily dose of 500 mg).

Data Collection.
A total of 1432 medical centers in Germany were involved in data collection in the original trial [17]. Physicians documented data on case report forms during consultation at three time points: baseline examination, treatment follow-up after 4-6 weeks, and at end of observation after approx. 3 months. Documentation included patient demographics, pain diagnosis, previous longterm analgesic treatment, concomitant diseases, the reason for prescribing tapentadol PR, tapentadol dosages, and concomitant analgesics and co-analgesics and adjuvants.
Patients were asked about their average pain intensity during the past 3 days, the course of pain over the previous 24 h, and impairments of sleep quality, quality of life, social activities, and independence in the previous 4 weeks. ey rated these outcome measures on an 11-point numerical rating scale (NRS-11), with 0 � no pain to 10 � worst imaginable pain for pain intensity and 0 � no impairment to 10 � maximally conceivable impairment for pain-related impairments. During baseline examination, physician and patient jointly decided on treatment targets to be achieved during the treatment period. Apart from a pain intensity target (NRS-11), they specified an additional-realistically achievable-individual treatment target from the following areas: quality of life, physical functioning, mental well-being, and others. At the end of observation, this target was rated by the patients using a goal attainment scale ("much better than expected," "better than expected," "as expected," "worse than expected," or "much worse than expected" [19]). Successful tapentadol PR treatment was determined by (a) attainment of at least 50% reduction in pain intensity, (b) attainment of intended pain intensity, (c) attainment of additional individual treatment target, and (d) attainment of (b) and/or (c) (combined response).
Tolerability was assessed by monitoring the occurrence of adverse drug reactions (ADRs; possibly, probably, or definitely related to the trial medication) during the entire observation period (query during visits and spontaneous reports by the patients). ese events were recorded on ADR documentation forms. Physicians did not make explicit causality evaluations. Completing the ADR documentation form implied that physicians assumed a causal relationship between the symptoms and tapentadol treatment; that is, they suspected an ADR.
At the end of treatment, physicians evaluated different aspects of tapentadol PR treatment (analgesia, tolerability, balance between efficacy and tolerability, compliance, quality of life, and overall treatment success), and both patients and physicians rated changes in the general condition of the patient since baseline examination.

Statistical Analysis.
For the original trial, completed case report forms were collected by the sponsor from the participating physicians and forwarded to factum GmbH (Offenbach, Germany) for data processing (double data entry) using the data management program DMSys (version 5.1., SigmaSoft International, Los Gatos, CA, USA) and data check (for completeness, consistency, and plausibility).
All patients with painful OA of the knee and/or hip participating in the original trial were stratified into an elderly age group (>65 years of age) and a younger age group (≤65 years of age). Data extraction and effectiveness analysis were performed by factum GmbH (Offenbach Germany) using the statistics program SPSS (version 15.0.0; SPSS Inc., Chicago, USA). Data were analyzed descriptively; percentages throughout the article are based on the total number of patients in the respective group (elderly, n � 752, or younger patients, n � 282) as denominator, unless otherwise stated. p values for changes in pain intensity, quality of sleep, quality of life, social activities, and independence over the course of the trial were calculated using Wilcoxon matched-pairs signed-rank test. Only patients with data at baseline and final visit were included in calculations for changes in these parameters and in calculations of treatment success criteria.

Patient Disposition and Demographics.
In total, 1038 patients (33.1% of the original trial population [effectiveness set n � 3134]) experienced painful OA. Stratification by age resulted in an elderly group (>65 years of age) of 752 patients (72.4%) and a younger group (≤65 years of age) of 282 patients (27.2%); information regarding age was not available for 4 patients.
us, 1034 patients were included in effectiveness and tolerability analyses. Table 1 lists the baseline characteristics of both groups. e majority of the elderly were female; gender was more balanced in the younger patient group. More than 55% of patients in both groups had experienced pain for more than two years. Many patients with painful knee and/or hip OA also suffered from other pain conditions, most commonly low back pain (LBP; elderly 83.9%/younger group 83.3%). e majority (94.2%/ 80.1%) also had concomitant diseases; cardiovascular (79.3%/46.5%) and metabolic disorders (41.8%/39.4%) were most common. Hospitalization due to pain during the 12 months prior to tapentadol PR treatment was documented for 29.7% (223/750) of the elderly and 23.5% (66/281) of the younger group.
Nearly all patients (98.7% [738/748]/99.3% [278/280]) had already received long-term analgesic treatment prior to the start of tapentadol PR treatment (Figure 1), mainly consisting of several analgesics ( Table 2). A higher proportion of elderly patients received transdermal fentanyl and buprenorphine compared with the younger group. Table 3 lists the different dosages of strong opioids used immediately prior to tapentadol initiation. In addition, 34.2% (256/748) of the elderly and 27.1% (76/280) of the younger patients took analgesic rescue medication (Table 4). Table 4 also lists the proportion of patients with co-analgesics and adjuvant medications.
Given that tapentadol was only available for use to physicians for a limited time period prior to the start of the trial, the doses used in this trial were conservative. Nevertheless, the intake of additional long-term analgesic medication could be reduced over the observation period (Figure 1). At the start of tapentadol PR treatment, 71.2%/ 71.5% of patients received additional long-term analgesics (mainly nonopioids), and 20.3% in both groups received only tapentadol PR, and 8.5%/8.2% received tapentadol PR plus rescue medication (n � 750/n � 281). At the end of observation, the proportion of patients with tapentadol PR monotherapy had increased to 32.2% and 36.8%, respectively, and an additional 12.9%/10.7% received tapentadol PR as only long-term medication plus analgesic rescue medication (n � 712/n � 272). Additional long-term analgesics consisted mainly of nonopioids ( Figure 1). Intake of rescue medication, antidepressants, antiepileptics, antiemetics, and laxatives had declined at the end of observation compared with data prior to tapentadol PR administration (Table 4).

Treatment Effects.
During the 3-month observation period, mean baseline pain intensity of 7.1 ± 1.5 for both groups was reduced by 3.8 points in the elderly (p ≤ 0.001; Figure 2(a)) and by 4.2 points in the younger group (p ≤ 0.001; Figure 2(b)). Pain relief was also observed over the course of 24 h. Fewer elderly patients experienced constant pain with pain attacks (53.1% before tapentadol PR treatment and 12.5% at the end of observation), and painfree intervals had markedly increased (from 6.1% to 51% of patients; ratings at both visits for 576 patients). e data for the younger age group showed a decrease in constant pain with pain attacks from 51.9% to 12.7%, and an increase in pain-free intervals from 8% to 60.9% (ratings at both visits for 212 patients).
At baseline examination, quality of sleep and all quality of life parameters were markedly impaired in both groups; Pain Research and Management social activities were affected most ( Figure 2). All had considerably improved at the end of observation: quality of sleep by 3 points (elderly) and by 3.6 points (younger patients), quality of life by 3.4/3.7 points, social activities by 3.0/3.7 points, and independence by 2.7/2.8 points (all p ≤ 0.001; Figure 2). e proportion of patients with uninterrupted sleep increased from 5.9% to 26.6% in the elderly (ratings at both visits for 542 patients) and from 4.1% to 30.3% in the younger group (ratings at both visits for 218 patients).

Treatment Success.
All four criteria for treatment success were attained by the majority of patients in both groups (Table 6). e mean targeted level of pain intensity at the end of the observation period as defined at baseline was 3.0 ± 1.2 by the elderly and 2.7 ± 1.5 by the younger group. is target was achieved or exceeded by 65 (Table 6).

Tolerability.
Sixty-three elderly patients (8.4%) and 18 patients in the younger age group (6.4%) experienced ADRs during tapentadol PR treatment. e most frequently reported incidences were gastrointestinal and nervous system disorders (Table 7). "Drug withdrawal syndrome" or "withdrawal syndrome" was noted for 4 patients, two of them elderly. e three patients receiving daily tapentadol PR doses over 500 mg did not experience ADRs. Serious ADRs were reported for 8 elderly patients (1.1%; 15 ADRs) and 2 younger patients (0.7%; 3 ADRs). In the elderly group, three patients had one ADR (fall, drug ineffective, and severe cardiac failure), four patients had two ADRs (severe diarrhea + severe sepsis, moderate abdominal pain upper + moderate nausea, ataxia + withdrawal syndrome, and moderate abdominal pain + colitis), and one patient had four moderate ADRs (abnormal sensation in eye, eye movement disorder, vision blurred, and visual impairment). In the younger age group, drug withdrawal syndrome was documented for one patient and severe fecaloma + severe ileus paralytic for a second patient.

Evaluation of Treatment.
At the end of observation, tapentadol PR treatment was rated "good" or "very good" for the majority of patients (

Discussion
e elderly OA patients analyzed here not only presented with painful knee and/or hip OA but also were afflicted by other pain conditions, most notably LBP. Many had been suffering from pain for more than 2 years, and almost all had received long-term analgesic medication before the start of tapentadol PR treatment. Despite this use of, often strong, analgesics (47% of patients were administered WHO III medication), the burden of pain was high: mean pain  Pain Research and Management intensity at baseline was rated as severe and accompanied by considerable impairments in sleep quality and daily functioning, and thus markedly reduced quality of life. Not surprisingly, the main reasons physicians opted for a switch to tapentadol PR were insufficient analgesia and quality of life with previous analgesic treatment. e 3-month treatment with tapentadol PR provided effective pain relief in both patient groups with slightly better outcomes in younger patients. However, a total of 68% of the elderly patients had clinically relevant pain reductions of at least 50% (vs baseline), and 65% achieved their intended pain intensity target. Mean pain intensity at the end of observation deviated by only 0.4 points from the mean treatment target of 3.0 points defined at baseline visit. e results are comparable to findings for the original trial population (72%/66% [17]) and the large population of a second 3-month noninterventional tapentadol PR trial (65%/60% [20]). Nausea, dizziness, and constipation were most frequently reported by the 8.4% of elderly patients experiencing ADRs during tapentadol PR treatment. Only 6.8% discontinued treatment due to the occurrence of an ADR. Physicians considered tapentadol PR treatment well tolerated by the majority of elderly patients, with "good" to "very good" ratings of over 80% in the following categories: gastrointestinal tolerability, CNS tolerability, and general tolerability.
Patients suffering from severe pain frequently complain about impairments in daily life such as diminished sleep quality, restrictions in social activities, and loss of independence. ese impairments may lead to social isolation, anxiety, and depression, and may thus greatly affect their quality of life. Results for Germany from the 2010 National Health and Wellness Survey showed that the impact of severe and frequent pain on the quality of life is greater than the contribution of sociodemographic factors, the presence      Pain Research and Management of comorbidities, or health risk factors such as obesity, alcohol, and smoking [21]. OA pain limits functionality. Physical activity is often restricted, which is considered a major factor in the onset of frailty in the elderly [22], resulting in a loss of independence and ultimately a move to a care facility. us, more so than in any other age group, pain relief in the elderly may, for some patients, be key to a longer independent and involved life. In addition, it is also likely to have an impact on the burden of care for their families and costs arising for society in general. ese impairments of functionality were observed in our elderly OA patients at baseline. ey presented with considerable impairments in sleep quality and quality of life at baseline, with social activities being the most severely impacted quality of life measure. Not surprisingly, the majority considered improvements in quality of life an important treatment target: 73% of the patients chose an additional individual treatment target from this domain. Effective pain relief under tapentadol PR treatment was accompanied by marked improvements in all quality of life measures which contributed to the overall treatment success of the medication. It should also be noted that one-third of the elderly patients (32.2%) did not require additional long-term analgesic medication at the end of observation and a further 12.9% received only tapentadol PR plus analgesic rescue medication. Elderly OA patients received mean daily tapentadol PR doses of 199 ± 101 mg, on average 14 mg less than the younger age group (213 ± 103 mg) at the end of observation and less than half the maximum recommended daily dose of 500 mg. is dosage was at the lower end of the mean daily dose range observed for other routine clinical practice tapentadol PR treatment data in cancer and noncancer pain (192-287 mg [17,20,[23][24][25][26][27]). In contrast, mean daily doses in phase 3 clinical trials were approx. 300 mg [3] and thus above the higher range found in noninterventional trials. Most of the clinical practice trials had been initiated when tapentadol PR was newly authorized and physicians had not yet gained experience with dosing this new analgesic. ey might thus have relied more on additional analgesics instead of using the full tapentadol PR dosing range. Adherence to dose adjustment recommendations available today might further improve therapeutic outcomes including a reduction in the requirement for additional long-term analgesics, an advantage for patients with polypharmacy.
Overall, tapentadol PR was effective and well tolerated in the treatment of painful OA in the elderly in routine clinical practice. e findings complement the positive results of tapentadol PR treatment in elderly patients ≥65 years and ≥75 years of age obtained in pooled analyses of randomized controlled clinical trials [12,13].
Analyses of routine clinical practice data are limited by the absence of a control group. However, our data which derived from a prospective, noninterventional trial where treatment decisions were solely at the discretion of the treating physician provide an insight into real-world pain management and complement the findings of randomized controlled trials with predefined trial criteria. For example, in contrast to randomized controlled trials with balanced group sizes, the proportion of elderly patients in our analysis was much higher (reflecting the real-life situation). However, this did not present a problem as no direct statistical comparison between groups was presented and the large number of patients in both groups allowed for a meaningful analysis within both. e lack in balance of potential confounding factors such as gender (higher proportion of women in elderly compared with younger age group) represents a limitation of our analysis, as this makes the groups not directly comparable to each other and might be reflected in the results of the two groups. However, the focus of our analysis was on the effectiveness and safety of tapentadol in elderly patients in a real-life situation in contrast to what is observed in younger patients in real-life rather than a direct comparison of tapentadol PR efficacy between both groups. It should be noted that most patients in this analysis not only suffered from painful OA but also from LBP. Data analysis could not distinguish between the two pathologies. e coexistence of these two pathologies is often observed in clinical practice and is not surprising, given that one could be caused by the other, for example, insufficient pain treatment of OA might lead to issues with posture resulting in subsequent complaints in other body regions such as the lower back.

Conclusion
Tapentadol PR provided effective and well-tolerated treatment of severe chronic OA pain for elderly patients in routine clinical practice. e marked improvements in all quality of life measures and the favorable tolerability profile in particular suggest tapentadol PR as an early treatment option before classical strong opioids are considered.

Abbreviations
ADR: Adverse drug reaction CR: Controlled release LBP: Low back pain NRS: Numerical rating scale OA: Osteoarthritis PR: Prolonged release WHO: World Health Organization.

Data Availability
On a case-by-case basis, the authors will share on request tables of the subgroup analysis.

Conflicts of Interest
AS is a consultant for Grünenthal GmbH, Germany; he participated in the study and received financial recompense for complete documentation of the patients. MS, BH, and CE are employees of Grünenthal GmbH.