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Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists a
Volker Strick a
Pain Clinic Rodenkirchen CologneGermany Published online: 26 May 2015.
Click for updates To cite this article: Volker Strick (2014) Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists, Current Medical Research and Opinion, 30:10, 2085-2092 To link to this article: http://dx.doi.org/10.1185/03007995.2014.939166
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Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.939166
Vol. 30, No. 10, 2014, 2085–2092
Article ST-0108.R1/939166 All rights reserved: reproduction in whole or part not permitted
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Original article Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists
Volker Strick
Abstract
Pain Clinic Rodenkirchen, Cologne, Germany Address for correspondence: Dr. Volker Strick, Ringstr. 2b, 50996 Ko¨ln, Germany. Tel.: +49 221 350240; [email protected] Keywords: Daily clinical pain specialist practice – Noninterventional study – Pain treatment – Severe chronic pain – Tapentadol PR Accepted: 24 June 2014; published online: 15 July 2014 Citation: Curr Med Res Opin 2014; 30:2085–92
Background and objective: Clinical trials have documented the efficacy and good tolerability of tapentadol prolonged released (PR) for severe chronic pain. This study investigated routine long-term administration by pain specialists. Methods: The effectiveness analysis included prospective data collected over a 3 month period (cohort I, n ¼ 1457, mean age 61.2 13 years) and over a 12 month period (cohort II, n ¼ 588, 60.1 13.2 years) regarding previous and concomitant analgesic treatment, tapentadol dosage, pain intensity, sleep and quality of life parameters, and tolerability. Results: Most patients (477%) had suffered from severe chronic pain for 2 years with low back pain the main pain diagnosis (82%); 91% had already received analgesic long-term treatment prior to initiation of tapentadol therapy (42% of those received strong opioids). After 3 month tapentadol treatment, cohort I had experienced a mean pain reduction of 2.4 points (from 6.8 1.6 at baseline) and improvements of 2.1 points in quality of sleep (from 5.8 2.5) and quality of life (from 6.5 2; all p 0.001). The 12 month tapentadol treatment (cohort II) reduced the mean pain intensity by 3.2 points from 6.7 1.6 at baseline (NRS-11; p 0.001); 57% of the patients experienced clinically relevant pain relief of 50%. At end of observation, 92% attained either their intended pain reduction and/or an additional individual treatment target, both predefined at start of tapentadol therapy. This was accompanied by a significant reduction in pain-related impairments in daily activities and an improvement in quality of life (all p 0.001). Most frequent side-effects were nausea (6.3% of patients) and dizziness (3.8%) for cohort I, and nausea (1.5%) and constipation (1.2%) for cohort II. Conclusion: Tapentadol PR is effective and well tolerated and can be considered an alternative to classical strong opioids in long-term chronic pain therapy. Limitations: The study lacks a control group; assessment under routine practice conditions, however, reflects daily practice clinical management conditions.
Introduction Chronic pain is a widespread problem interfering significantly with the daily life of people affected: persistent pain, either continuous or recurrent, of sufficient duration and intensity may have a significant impact on a patient’s level of functioning, overall well-being and quality of life. Chronic pain can be classified as ! 2014 Informa UK Ltd www.cmrojournal.com
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nociceptive pain (after tissue trauma with intact peripheral and central pain system), neuropathic pain (damaged peripheral and/or central pain system), or mixed pain (nociceptive and neuropathic pain components). Opioid analgesics are often the only treatment option for severe chronic pain. A disadvantage of classical opioids are tolerability issues in long-term treatment which frequently result in reduced quality of life, gastrointestinal or central nervous system side effects and withdrawal from treatment1. Thus, it is deemed important to find the right balance between effective analgesia and good tolerability. Tapentadol prolonged release (PR; Palexia retard*) combines an opioidergic and a noradrenergic component in one molecule, and both mechanisms – m-opioid receptor binding and inhibition of noradrenaline reuptake – contribute synergistically to the analgesic efficacy of the compound, whilst at the same time reducing typical opioid side effects2. Efficacy and good tolerability of tapentadol PR in the treatment of severe chronic pain of different etiologies have been documented in clinical studies3,4 and three 3 month observational studies5–7. In this observational study, patients were documented beyond a 3 month period, thus providing long-term data of up to 12 months of routine administration in pain specialist centers.
Patients and methods Taking into account a balanced geographical distribution, 230 pain specialists practicing in Germany participated in this prospective, non-interventional study. A noninterventional study design complements randomized clinical studies which have a primarily homogeneous patient population and assesses the routine administration of medications under practice conditions in a heterogeneous patient population. Thus, a non-interventional study more likely reflects real life clinical management conditions. The study was performed between October 2010 and June 2012 in accordance with section 4, subsection 23, clause 3 and section 67, subsection 6 of the Medicinal Products Act of the Federal Republic of Germany. All treatment decisions were solely at the treating physician’s discretion. Tapentadol PR was prescribed in accordance with the summary of product characteristics (initial dose 2 50 to 2 250 mg/day depending on previous treatment and pain severity)8. A dose adjustment within 3 days was recommended in case of insufficient pain relief.
Data collection Data were documented by the pain specialist in case report forms during consultation at the following six predefined observation times: baseline examination, treatment *Palexia retard is a registered trademark of Gru¨nenthal GmbH, Aachen, Germany
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follow-up after 4–6 weeks and 3, 6 and 9 months, and at end of observation after approximately 12 months. Documentation included patient demographics, concomitant diseases and previous analgesic treatment, pain diagnosis, the reason for prescribing tapentadol PR, tapentadol dosages, and analgesic and other concomitant medications. In addition, patients were asked about their average pain intensity during the last 3 days, the daily pain pattern (24 h), and impairments of sleep quality, quality of life, social activities, independence, and libido in the previous 4 weeks. Pain intensity and any pain-related impairments were rated on an 11-point numerical rating scale (NRS11). In addition, physician and patient jointly decided on treatment targets during baseline examination which were to be achieved during the treatment period. They agreed on a pain intensity target (NRS-11) and selected an additional –realistically achievable – individual treatment target from the areas quality of life, physical functioning, mental well-being and others which was rated at end of observation by the patients as ‘much better than expected’, ‘better than expected’, ‘as expected’, ‘worse than expected’ and ‘much worse than expected’9. Attainment of one or both of these treatment targets (‘and/or’, combined response rate) and attainment of at least 50% reduction in pain intensity were used as effectiveness criteria for treatment success. In order to assess tolerability of tapentadol PR, physicians monitored the occurrence of adverse drug reactions (ADRs) during the entire observation period (query during visits, spontaneous reports by the patients). ADRs were recorded on ADR documentation forms.
Statistical analysis Documented data were processed by factum GmbH (Offenbach, Germany) with double data entry using the data management program DMSys (version 5.1; SigmaSoft International, Los Gatos, CA, USA). All data were checked for completeness, consistency and plausibility. Effectiveness was analyzed with SPSS (version 15.0.0; SPSS Inc., Chicago, IL, USA) using two effectiveness populations: all prospectively documented patients with case report forms for the first three treatment months (cohort I) and all patients with data for the entire 12 month observation (cohort II). Descriptive p-values for changes over the course of the study in mean pain intensity and in sleep quality and quality of life parameters were calculated by Wilcoxon rank tests. The safety and tolerability analysis was performed by PHARMSOFT Dr. B. Rodust GmbH (Ascheberg, Germany). ADRs were encoded with the Medical Dictionary for Regulatory Activities (MedDRA, version 15.0). www.cmrojournal.com ! 2014 Informa UK Ltd
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Results A total of 1457 patients were included in the effectiveness analysis of the first 3 months (cohort I); data for the 12 month observation period were available for 588 of the patients (cohort II). The results of both analyses are described separately.
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Effectiveness analysis cohort I (3 month observation) Table 1 summarizes the baseline data of the patients. Concomitant diseases were documented for 70.6% of the patients; cardiovascular (43.5%) and metabolic diseases (23.3%) were most common. The main pain diagnosis was low back pain (82%); 55.7% of these patients reported a radicular pain radiation. A total of 73.5% of the patients suffered from mixed pain; 13% had predominantly nociceptive and 6.5% predominantly neuropathic pain. The majority of patients had a duration of pain of more than 2 years (77.1%), and 25.3% had been hospitalized owing to pain during the 12 months prior to start of tapentadol therapy. Most patients (90.9%) had already received long-term analgesic treatment prior to the start of tapentadol Table 1. Demographic data and pain diagnoses of the two effectiveness patient populations.
Gender (male/female) Age (years) Duration of pain 51–3 months 43–6 months 40.5–1 year 41–2 years 42 years Type of pain Predominantly nociceptive pain Predominantly neuropathic pain Mixed pain Unknown/no data Pain diagnosisa Low back pain Primary causes Intervertebral disc degeneration Spondylarthrosis Spinal stenosis Osteoporosis Further causes of pain Gonarthrosis Coxarthrosis Diabetic polyneuropathy Stroke or trauma Tumor Postherpetic neuralgia Other causes
Cohort I (n ¼ 1457)
Cohort II (n ¼ 588)
37.5%/62.4% 61.2 13.0
36.9%/63.1% 60.1 13.2
43 (3) 68 (4.7) 91 (6.3) 128 (8.8) 1123 (77.1)
10 (1.7) 33 (5.6) 32 (5.4) 51 (8.7) 462 (78.6)
190 (13.0) 94 (6.5) 1071 (73.5) 102 (7.0)
85 (14.5) 50 (8.5) 410 (69.7) 43 (7.3)
1195 (82)
485 (82.5)
596 (40.9)
252 (42.9)
449 (30.8) 298 (20.5) 122 (8.4) 811 (55.7) 289 (19.8) 183 (12.6) 81 (5.6) 63 (4.3) 43 (3) 32 (2.2) 352 (24.2)
190 (32.3) 123 (20.9) 55 (9.4) 322 (54.8) 115 (19.6) 65 (11.1) 40 (6.8) 28 (4.8) 14 (2.4) 15 (2.6) 133 (22.6)
Data are number of patients (%) except for age (mean SD). a Multiple responses permitted.
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treatment, mainly consisting of several analgesics; 1.6% of the patients were taking pain medication as required, and 7.3% did not receive prior analgesic therapy (no data for four patients). Table 2 shows the immediate analgesic therapy preceding tapentadol PR treatment. Overall 22.1% of all patients received analgesics as required, in the majority of cases in addition to long-term pain therapy. The use of antidepressants (36.4%), antiepileptics (32.1%), laxatives (17.2%) and antiemetics (8.2%) was also documented.
Treatment with tapentadol PR Patients were switched to tapentadol PR mainly owing to insufficient pain relief (84.6%) or insufficient quality of life (63.7%) (multiple responses permitted). Additional reasons were insufficient overall tolerability (26.2%), insufficient balance between effectiveness and tolerability (25.4%), interactions with concomitant medications (4.6%), and a lack of compliance (4.1%). In 73.8% of the patients tapentadol PR treatment was initiated using 2 50 mg/day; 15.8% received an initial dose of 2 100 mg/day and 6.3% of at least 2 150 mg/ day. The mean daily dosage was 131.7 67.1 mg at start of therapy, 204.4 118.4 mg at the end of the titration phase and 227.1 131.2 mg after the 3 month observation. The mean duration of treatment was 81.3 37.1 days for this cohort; 71.1% of the patients continued treatment. At treatment initiation with tapentadol PR 47.8% of the patients still received additional long-term medication (6.5% strong opioids, 3.6% weak opioids, 43% nonopioids; multiple responses permitted); this proportion was reduced to 35.7% (7.4% strong opioids, 2.8% weak opioids, 31.6% non-opioids) at the end of 3 months. Oxycodone/naloxone and oxycodone (both 1.7%) as well as morphine (1.6%) were the most frequently Table 2. Analgesic medication immediately preceding therapy with tapentadol PR (n ¼ 1457). WHO III analgesicsa Oxycodone/naloxone Oxycodone Hydromorphone Buprenorphine Fentanyl (transdermal) Morphine Other Weak opioidsa Tilidine/naloxone Tramadol Other Non-opioidsa Nonsteroidal anti-inflammatory drugs Metamizole Muscle relaxants Other
608 (41.7) 139 (9.5) 129 (8.6) 114 (7.8) 92 (6.3) 91 (6.3) 79 (5.4) 12 (0.8) 507 (34.8) 284 (19.5) 242 (16.6) 2 (0.1) 881 (60.5) 516 (35.4) 245 (16.8) 230 (15.8) 161 (11.1)
Data are number of patients (%). a Multiple responses permitted.
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Mean pain intensity in the last three days (NRS 0–10)
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10 9
Baseline visit
End of observation
8 7
6.8
6.7
6 5
4.4* 3.5*
4 3 2 1 0
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Cohort I (3 months) n=1351
Cohort II (12 months) n=565
Figure 1. Reduction in mean pain intensity under tapentadol PR therapy. Only patients with data for both observation times were included. NRS, 11-point numerical rating scale. *p 0.001 (descriptive) compared to baseline visit (Wilcoxon rank test).
prescribed strong opioids. At end of observation, exclusive long-term analgesic treatment with tapentadol PR was reported for 46.4% of the patients; 9.9% received medication as required in addition to tapentadol PR (no data for 8%). Treatment effects During the 3 month observation period, pain intensity was reduced by 2.4 points to 4.4 2.2 (Figure 1). A total of 38.1% of the patients achieved a pain reduction of at least 50%, and 38.3% attained their pain intensity target of 3.0 1.3 determined at baseline (data for n ¼ 1351). Quality of sleep and quality of life both improved by 2.1 points from 5.8 2.5 to 3.7 2.5, and from 6.5 2 to 4.3 2.4, respectively; impairments in social activities improved by 2.2 points from 6.6 2.4 to 4.4 2.6, independence by 1.7 points from 4.9 2.7 to 3.2 2.5, and libido by 1.2 points from 5.7 3.6 to 4.5 3.4 (all descriptive p 0.001). The most frequently selected additional individual treatment targets derived from the areas of quality of life (69.2%) and physical functioning (46.8%). At end of observation, 75.1% of the patients with data (n ¼ 1314) had achieved their individual treatment target. The combined response rate was 74.3% (data for n ¼ 1361).
Effectiveness analysis cohort II (12 month observation) Demographic and medical history characteristics of this cohort were comparable to cohort I (Table 1). Apart from a slightly lower proportion of patients under longterm metamizole therapy (16.8% vs. 12.9%), there were 2088
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no considerable differences to cohort I regarding immediate long-term medication preceding tapentadol therapy and regarding the reasons for prescribing tapentadol PR. The mean tapentadol PR dose at start of treatment was 130.8 63.8 mg/day, increased slightly more than in cohort I after titration (218.2 119.6 mg/day vs. 204.4 118.4 mg/day), and was 245.8 122.3 mg (229.7 119.3 in cohort I) after 4–6 weeks. Dosages further increased during a mean treatment duration of 348.2 69.4 days by on average 26.8 mg to 272.6 139.5 mg/day. Most patients (80.1%) continued treatment after the 12 month observation period. At end of observation, 45.9% of the patients received long-term monotherapy with tapentadol PR; 15.5% received additional analgesics as required (no data for 6.8%). The proportion of patients requiring additional long-term pain medication decreased to 31.1% (Figure 2). Less patients than in the 3 month cohort were administered additional strong opioids (3.2% vs. 7.4%); most common among those were morphine (1%), oxycodone/naloxone (0.7%) and oxycodone (0.5%). The proportion of patients with antiemetics declined from 17.7% to 4.9% (no data for 7.5%). Pain relief Mean pain intensity was 6.7 1.6 at baseline and was reduced by 3.2 points to 3.5 2.1 over the 12 month observation period (Figure 1). Pain relief was also observed during the daily course over 24 h. Fewer patients suffered from constant pain with pain attacks (34.6% before treatment initiation, 19.7% at end of observation) or intermittent pain attacks with painful intervals (7.3% to 2.4%). The proportion of patients with pain-free intervals increased from 8.2% to 24.3%. Pain relief and tapentadol dosages over the 12 month observation period were also analyzed for patients for whom data for all observation times were available (start of treatment, after 3, 6 and 9 months, and at end of observation) and who continued tapentadol treatment after 12 months (n ¼ 455). Mean pain intensity prior to tapentadol treatment was 6.7 1.6 points. Figure 3 shows a marked reduction in pain intensity during the first 3 months followed by further improvements (overall 3.5 points) under relatively stable tapentadol dosages after dose adjustments. Quality of sleep and quality of life At the end of the 12 month observation all assessed parameters showed marked improvements compared to baseline (Figure 4). Pain-related impairments in quality of life improved as follows: social activities by 3.5 points, quality of life by 3.4 points, quality of sleep by 3.1 points, and independence and libido both by 2.6 points. The frequency of waking up during the night owing to pain also decreased. At baseline, 64.5% of patients reported waking up at least www.cmrojournal.com ! 2014 Informa UK Ltd
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Proportion of patients (%)
100
91%
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Immediate pretreatment
90
Treatment initiation
80
End of observation
70 59% 60 48%
50 40
45%
42% 36%
32%
29%
30 20 10
4% 3%
4% 3%
0 Non-opioids
Weak opioids
Strong opioids
Figure 2. Long-term analgesics immediately preceding the start of tapentadol treatment and in addition to tapentadol PR during the 12 month observation period (cohort II, n ¼ 588). Multiple responses permitted.
253
9
263
273
275
300 250
8 7 6
6.7
5
129
200 150
4 3.7
3
3.8
3.4
100 3.2
2
50
Mean tapentadol dose (mg/day)
10 Mean pain intensity (NRS 0–10)
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Total
1 0
0 Start
3
6
9
12
Treatment (months)
Figure 3. Tapentadol PR dose stability and reduction of pain intensity during the 12 month observation period (n ¼ 455). Only patients with data for all observation times were included. NRS, 11-point numerical rating scale.
twice during the night whereas this was only reported by 22.3% at end of observation. The proportion of patients with uninterrupted sleep increased from 9.4% to 34.7%.
Treatment success A total of 56.5% of patients had a reduction in pain intensity of at least 50% at end of observation (Figure 5). They had stated a mean pain intensity of 2.93 1.2 as intended treatment target at baseline visit; after 12 months, mean pain intensity was 3.49 2.1. Overall, 54.3% achieved their intended pain reduction. The most frequently selected additional individual treatment targets derived from the areas quality of life (65.3%) and physical functioning (47.5%). At end of observation 88.8% of patients had reached or exceeded their individual treatment target: 15.6% rated ‘much better than expected’, 40.1% ‘better ! 2014 Informa UK Ltd www.cmrojournal.com
than expected’, and 33% ‘as expected’. The combined response rate was 92.3%.
Tolerability In addition to the 1509 patients with case report forms, 28 patients without effectiveness data but ADR documentation were included in the tolerability analysis (n ¼ 1537; safety population). A total of 331 patients (21.5%) experienced 737 ADRs. Of these, 95.9% were not serious and 79% were known for tapentadol PR. The most frequent ADRs (for 410 patients) were nausea (96 patients/6.3%), dizziness (58/3.8%), fatigue (44/2.9%), hyperhidrosis (32/2.1%), vomiting (31/2%), headache (21/1.4%), constipation (20/1.3%), somnolence (20/1.3%), restlessness (19/1.2%), upper abdominal pain (17/1.1%), pruritus (16/1%), diarrhea (15/1%), tremor (13/0.9%), dry mouth (12/0.8%) and sleep disturbances (11/0.7%). Among the 588 patients with 12 month data 94 ADRs were documented for 53 patients (9%). Of these, 97.9% were not serious and 77.7% were known for tapentadol PR. Nausea (9 patients, 1.5%), constipation (7/1.2%), dizziness (6/1.1%), and hyperhidrosis and headache (both 5/0.9%) were most frequent.
Discussion The majority of patients described here already had a long pain duration; 79% of the patients with 12 month data had been suffering for more than 2 years from severe chronic pain. Despite long-term treatment with several, often strong analgesics (42% of patients received WHO III medication) the burden of pain at baseline visit was high Long-term chronic pain treatment with tapentadol PR Strick
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Mean impairment (NRS 0–10)
10 Baseline visit
9
End of observation
8
6
6.7
6.5
7 5.9
5.8 4.9
5 4 3
3.2*
3.1*
2.8*
3.2* 2.3*
2 1 0
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Sleep quality n=531
Quality of life n=538
Social activities n=528
Independence n=523
Libido n=442
Figure 4. Impairment of quality of sleep and quality of life parameters (during the previous 4 weeks) over the 12 month observation period (cohort II). Only patients with data for both observation time points were included. NRS, 11-point numerical rating scale. *p 0.001 (descriptive) compared to baseline visit (Wilcoxon rank test).
At least 50% pain reduction
56.5% (n=565)
Attainment of pain intensity target
54.3% (n=565)
Attainment of additional individual treatment target
88.8% (n=563)
Combined response rate
92.3% (n=586) 0
20 40 60 80 Proportion of patients (%)
100
Figure 5. Proportion of patients who attained one or several therapy targets at the end of the 12 month observation period (cohort II, n ¼ 588). Combined response rate, attainment of intended pain reduction and/or of the additional individual therapy target.
and the main reasons for switching medication were insufficient pain relief and reduced quality of life of the patients. Long-term treatment with tapentadol PR resulted in an effective pain reduction for a broad range of pain diagnoses including nociceptive pain (caused e.g. by gonarthrosis or coxarthrosis), neuropathic pain (e.g. postherpetic neuralgia) or mixed pain (back or tumor pain). After 12 months of treatment 57% of patients had clinically relevant pain relief of at least 50%. Furthermore, additional long-term analgesic treatment was markedly reduced and 46% of patients were exclusively treated with tapentadol PR. The intended mean treatment target of 2.9 points (determined by the patients at baseline on the pain scale) was achieved or exceeded by 54% of patients. Overall, mean pain intensity at end of observation was 0.6 points higher than hoped for. This treatment target was probably too ambitious for this patient population with long pain duration and previous long-term analgesic treatment consisting of often several pain medications. The pain reduction observed here was accomplished without using the maximum permitted tapentadol dosages; 2090
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treatment success might thus be further improved. The mean daily dosage of 273 140 mg after 12 months was markedly lower than the permitted maximum dose of 500 mg/day. These doses were also lower than the ones administered in a randomized clinical safety study which assessed tapentadol long-term therapy for chronic low back or osteoarthritis pain10. In this study, all patients who completed the study received on average 381 102 mg tapentadol PR/day. As in the current observation, a mean pain reduction of 3.2 points was observed. The authors of the safety study could not find any indication for acquired tolerance within the tested dose range in patients treated for a year with tapentadol PR. Following initial dose adjustments during the first 4–6 weeks, there were also only small changes in daily dosages during the 1 year assessment period of this study and tapentadol was associated with reliable pain relief. Severe pain can result in impairments in daily life such as restrictions in social activities and quality of sleep, loss of independence, anxiety, depression and reduced quality of life; these impairments increase with increasing pain www.cmrojournal.com ! 2014 Informa UK Ltd
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chronification11. Restoring or preserving a patient’s autonomy and quality of life is therefore a matter of priority for modern pain management. Treatment with tapentadol PR showed marked improvements in social activities, independence, libido, quality of sleep, and quality of life. A total of 89% of the patients achieved their additional individual treatment target which could be selected from different areas of daily life. The treatment success can also be gauged from the combined response rate: 92% of all patients attained their intended pain reduction and/or their additional individual treatment target. The analysis of the larger patient population (cohort I, n ¼ 1457) showed a level of pain relief over the 3 month observation period which is comparable to randomized clinical studies3. As expected, treatment success for patients consulting a pain specialist was not as high after 3 months as for patients in general practice or patients treated by specialists for internal medicine5. Patients treated by a pain specialist usually had already suffered from severe chronic pain for a long time (77% for more than 2 years compared to 48% in general practice), could not be adequately treated by general practitioners and had still not experienced sufficient pain relief following conservative treatment by the pain specialist with often strong analgesics. Pain relief with tapentadol PR could be further improved in these patients during the next 9 months. Overall, tapentadol PR treatment was well tolerated. Adverse drug reactions were documented for approx. 1/5 (21.5%) of all patients of the entire safety population (n ¼ 1537); 9% of the patients under long-term treatment (12 months; n ¼ 588) were affected. The most frequent side effects were often typical for opioids. Overall, when administering tapentadol, there is, however, a significantly lower risk for typical opioid side effects such as nausea, vomiting, constipation, dizziness, somnolence, and pruritus, as was shown in randomized, controlled comparative studies of tapentadol and oxycodone12–14. The findings from the present daily clinical practice observation regarding tolerability did not lead to changes in the qualitative or quantitative risk profile of tapentadol PR.
Conclusion Pain treatment with tapentadol PR in daily clinical practice resulted in an effective reduction of severe chronic pain also under long-term administration in a broad range of indications accompanied by marked improvements in quality of sleep and quality of life.
Consequences for clinical practice Tapentadol PR can be administered in patients with a long pain duration and thus far insufficient pain relief. ! 2014 Informa UK Ltd www.cmrojournal.com
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Apart from pain control, pain-related impairments in daily life and quality of life can be improved. Tapentadol PR can be administered for a broad range of pain indications. Tapentadol PR is very effective and at the same time well tolerated and can be considered an alternative therapy to classical strong opioids for long-term chronic pain management.
Transparency Declaration of funding This study was supported by Gru¨nenthal GmbH, Aachen, Germany. Declaration of financial/other relationships V.S. has disclosed that he is an advisor for Gru¨nenthal GmbH. He participated in this study and received financial recompense for complete documentation of patients. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments The author thanks all participating physicians, and Elke Grosselindemann and Birgit Brett for writing and editorial assistance. All costs in connection with the preparation of the manuscript were met by Gru¨nenthal GmbH. Previous presentation: Part of the manuscript data was presented in two posters at the German Pain Conference, Hamburg, 23–26 October 2013: Friedrich J, Lehmann U, Schwenke K. Tapentadol PR in daily clinical practice – longterm data from pain specialists (in German). Schmerz 2013;27(Suppl 1):114; Lehmann U, Friedrich J, WaldmannRex S, Schwenke K. Tapentadol PR in daily clinical practice – treatment success in general practice, pain practice and orthopedic practice (in German). Schmerz 2013;27(Suppl 1):114
References 1. Kalso E. The vicious circle in chronic pain management: balancing efficacy and adverse effects. Curr Med Res Opin 2011;27:2069-71 2. Tzschentke TM, De Vry J, Terlinden R, et al. Tapentadol hydrochloride. Analgesic, mu-opioid receptor agonist, noradrenaline reuptake inhibitor. Drugs Future 2006;31:1053-61 3. Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician 2013;16:27-40 4. Mercadante S, Porzio G, Ferrera P, et al. Tapentadol in cancer pain management: a prospective open-label study. Curr Med Res Opin 2012;28:1775-9 5. Schwittay A, Schumann C, Litzenburger B, Schwenke K. Tapentadol prolonged release for severe chronic pain: results of a noninterventional study involving general practitioners and internists. J Pain Palliat Care Pharmacother 2013;27:225-34 6. Strohmeier M, Waldmann-Rex S, Schwenke K. Influence of tapentadol retard on functional parameters in patients with severe chronic pain – is there a benefit in daily life? (In German) MMW Fortschr Med 2013;155:63-71 7. Agbalaka A, Schwenke K, Litzenburger B. Tapentadol prolonged release for the treatment of severe chronic tumor pain in routine clinical practice. (In German.) MMW Fortschr Med 2012;154:123-30
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12. Buynak R, Shapiro DY, Okamoto A, et al. 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. Expert Opin Pharmacother 2010;11: 1787-804 13. Lange B, Kuperwasser B, Okamoto A, et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010;27:381-99 14. Merker M, Dinges G, Koch T, et al. Undesired side effects of tapentadol in comparison to oxycodone. A meta-analysis of randomized controlled comparative studies. (In German.) Schmerz 2012;26:16-26
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8. Gru¨nenthal GmbH. Fachinformation Palexia retard (German summary of product characteristics). Gru¨nenthal GmbH, November 2012 9. Kiresuk TJ, Sherman RE. Goal attainment scaling: a general method for evaluating comprehensive community mental health programs. Community Ment Health J 1968;4:443-53 10. Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract 2010;10:416-27 11. Frettlo¨h J, Maier C, Gockel H, Hu¨ppe M. Validation of the German Mainz Pain Staging System in different pain syndromes. (In German.) Schmerz 2003;17:240-51
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Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists a
Volker Strick a
Pain Clinic Rodenkirchen CologneGermany Published online: 26 May 2015.
Click for updates To cite this article: Volker Strick (2014) Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists, Current Medical Research and Opinion, 30:10, 2085-2092 To link to this article: http://dx.doi.org/10.1185/03007995.2014.939166
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Original article Management of severe chronic pain with tapentadol prolonged release – long-term data from pain specialists
Volker Strick
Abstract
Pain Clinic Rodenkirchen, Cologne, Germany Address for correspondence: Dr. Volker Strick, Ringstr. 2b, 50996 Ko¨ln, Germany. Tel.: +49 221 350240; [email protected] Keywords: Daily clinical pain specialist practice – Noninterventional study – Pain treatment – Severe chronic pain – Tapentadol PR Accepted: 24 June 2014; published online: 15 July 2014 Citation: Curr Med Res Opin 2014; 30:2085–92
Background and objective: Clinical trials have documented the efficacy and good tolerability of tapentadol prolonged released (PR) for severe chronic pain. This study investigated routine long-term administration by pain specialists. Methods: The effectiveness analysis included prospective data collected over a 3 month period (cohort I, n ¼ 1457, mean age 61.2 13 years) and over a 12 month period (cohort II, n ¼ 588, 60.1 13.2 years) regarding previous and concomitant analgesic treatment, tapentadol dosage, pain intensity, sleep and quality of life parameters, and tolerability. Results: Most patients (477%) had suffered from severe chronic pain for 2 years with low back pain the main pain diagnosis (82%); 91% had already received analgesic long-term treatment prior to initiation of tapentadol therapy (42% of those received strong opioids). After 3 month tapentadol treatment, cohort I had experienced a mean pain reduction of 2.4 points (from 6.8 1.6 at baseline) and improvements of 2.1 points in quality of sleep (from 5.8 2.5) and quality of life (from 6.5 2; all p 0.001). The 12 month tapentadol treatment (cohort II) reduced the mean pain intensity by 3.2 points from 6.7 1.6 at baseline (NRS-11; p 0.001); 57% of the patients experienced clinically relevant pain relief of 50%. At end of observation, 92% attained either their intended pain reduction and/or an additional individual treatment target, both predefined at start of tapentadol therapy. This was accompanied by a significant reduction in pain-related impairments in daily activities and an improvement in quality of life (all p 0.001). Most frequent side-effects were nausea (6.3% of patients) and dizziness (3.8%) for cohort I, and nausea (1.5%) and constipation (1.2%) for cohort II. Conclusion: Tapentadol PR is effective and well tolerated and can be considered an alternative to classical strong opioids in long-term chronic pain therapy. Limitations: The study lacks a control group; assessment under routine practice conditions, however, reflects daily practice clinical management conditions.
Introduction Chronic pain is a widespread problem interfering significantly with the daily life of people affected: persistent pain, either continuous or recurrent, of sufficient duration and intensity may have a significant impact on a patient’s level of functioning, overall well-being and quality of life. Chronic pain can be classified as ! 2014 Informa UK Ltd www.cmrojournal.com
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nociceptive pain (after tissue trauma with intact peripheral and central pain system), neuropathic pain (damaged peripheral and/or central pain system), or mixed pain (nociceptive and neuropathic pain components). Opioid analgesics are often the only treatment option for severe chronic pain. A disadvantage of classical opioids are tolerability issues in long-term treatment which frequently result in reduced quality of life, gastrointestinal or central nervous system side effects and withdrawal from treatment1. Thus, it is deemed important to find the right balance between effective analgesia and good tolerability. Tapentadol prolonged release (PR; Palexia retard*) combines an opioidergic and a noradrenergic component in one molecule, and both mechanisms – m-opioid receptor binding and inhibition of noradrenaline reuptake – contribute synergistically to the analgesic efficacy of the compound, whilst at the same time reducing typical opioid side effects2. Efficacy and good tolerability of tapentadol PR in the treatment of severe chronic pain of different etiologies have been documented in clinical studies3,4 and three 3 month observational studies5–7. In this observational study, patients were documented beyond a 3 month period, thus providing long-term data of up to 12 months of routine administration in pain specialist centers.
Patients and methods Taking into account a balanced geographical distribution, 230 pain specialists practicing in Germany participated in this prospective, non-interventional study. A noninterventional study design complements randomized clinical studies which have a primarily homogeneous patient population and assesses the routine administration of medications under practice conditions in a heterogeneous patient population. Thus, a non-interventional study more likely reflects real life clinical management conditions. The study was performed between October 2010 and June 2012 in accordance with section 4, subsection 23, clause 3 and section 67, subsection 6 of the Medicinal Products Act of the Federal Republic of Germany. All treatment decisions were solely at the treating physician’s discretion. Tapentadol PR was prescribed in accordance with the summary of product characteristics (initial dose 2 50 to 2 250 mg/day depending on previous treatment and pain severity)8. A dose adjustment within 3 days was recommended in case of insufficient pain relief.
Data collection Data were documented by the pain specialist in case report forms during consultation at the following six predefined observation times: baseline examination, treatment *Palexia retard is a registered trademark of Gru¨nenthal GmbH, Aachen, Germany
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follow-up after 4–6 weeks and 3, 6 and 9 months, and at end of observation after approximately 12 months. Documentation included patient demographics, concomitant diseases and previous analgesic treatment, pain diagnosis, the reason for prescribing tapentadol PR, tapentadol dosages, and analgesic and other concomitant medications. In addition, patients were asked about their average pain intensity during the last 3 days, the daily pain pattern (24 h), and impairments of sleep quality, quality of life, social activities, independence, and libido in the previous 4 weeks. Pain intensity and any pain-related impairments were rated on an 11-point numerical rating scale (NRS11). In addition, physician and patient jointly decided on treatment targets during baseline examination which were to be achieved during the treatment period. They agreed on a pain intensity target (NRS-11) and selected an additional –realistically achievable – individual treatment target from the areas quality of life, physical functioning, mental well-being and others which was rated at end of observation by the patients as ‘much better than expected’, ‘better than expected’, ‘as expected’, ‘worse than expected’ and ‘much worse than expected’9. Attainment of one or both of these treatment targets (‘and/or’, combined response rate) and attainment of at least 50% reduction in pain intensity were used as effectiveness criteria for treatment success. In order to assess tolerability of tapentadol PR, physicians monitored the occurrence of adverse drug reactions (ADRs) during the entire observation period (query during visits, spontaneous reports by the patients). ADRs were recorded on ADR documentation forms.
Statistical analysis Documented data were processed by factum GmbH (Offenbach, Germany) with double data entry using the data management program DMSys (version 5.1; SigmaSoft International, Los Gatos, CA, USA). All data were checked for completeness, consistency and plausibility. Effectiveness was analyzed with SPSS (version 15.0.0; SPSS Inc., Chicago, IL, USA) using two effectiveness populations: all prospectively documented patients with case report forms for the first three treatment months (cohort I) and all patients with data for the entire 12 month observation (cohort II). Descriptive p-values for changes over the course of the study in mean pain intensity and in sleep quality and quality of life parameters were calculated by Wilcoxon rank tests. The safety and tolerability analysis was performed by PHARMSOFT Dr. B. Rodust GmbH (Ascheberg, Germany). ADRs were encoded with the Medical Dictionary for Regulatory Activities (MedDRA, version 15.0). www.cmrojournal.com ! 2014 Informa UK Ltd
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Results A total of 1457 patients were included in the effectiveness analysis of the first 3 months (cohort I); data for the 12 month observation period were available for 588 of the patients (cohort II). The results of both analyses are described separately.
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Effectiveness analysis cohort I (3 month observation) Table 1 summarizes the baseline data of the patients. Concomitant diseases were documented for 70.6% of the patients; cardiovascular (43.5%) and metabolic diseases (23.3%) were most common. The main pain diagnosis was low back pain (82%); 55.7% of these patients reported a radicular pain radiation. A total of 73.5% of the patients suffered from mixed pain; 13% had predominantly nociceptive and 6.5% predominantly neuropathic pain. The majority of patients had a duration of pain of more than 2 years (77.1%), and 25.3% had been hospitalized owing to pain during the 12 months prior to start of tapentadol therapy. Most patients (90.9%) had already received long-term analgesic treatment prior to the start of tapentadol Table 1. Demographic data and pain diagnoses of the two effectiveness patient populations.
Gender (male/female) Age (years) Duration of pain 51–3 months 43–6 months 40.5–1 year 41–2 years 42 years Type of pain Predominantly nociceptive pain Predominantly neuropathic pain Mixed pain Unknown/no data Pain diagnosisa Low back pain Primary causes Intervertebral disc degeneration Spondylarthrosis Spinal stenosis Osteoporosis Further causes of pain Gonarthrosis Coxarthrosis Diabetic polyneuropathy Stroke or trauma Tumor Postherpetic neuralgia Other causes
Cohort I (n ¼ 1457)
Cohort II (n ¼ 588)
37.5%/62.4% 61.2 13.0
36.9%/63.1% 60.1 13.2
43 (3) 68 (4.7) 91 (6.3) 128 (8.8) 1123 (77.1)
10 (1.7) 33 (5.6) 32 (5.4) 51 (8.7) 462 (78.6)
190 (13.0) 94 (6.5) 1071 (73.5) 102 (7.0)
85 (14.5) 50 (8.5) 410 (69.7) 43 (7.3)
1195 (82)
485 (82.5)
596 (40.9)
252 (42.9)
449 (30.8) 298 (20.5) 122 (8.4) 811 (55.7) 289 (19.8) 183 (12.6) 81 (5.6) 63 (4.3) 43 (3) 32 (2.2) 352 (24.2)
190 (32.3) 123 (20.9) 55 (9.4) 322 (54.8) 115 (19.6) 65 (11.1) 40 (6.8) 28 (4.8) 14 (2.4) 15 (2.6) 133 (22.6)
Data are number of patients (%) except for age (mean SD). a Multiple responses permitted.
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treatment, mainly consisting of several analgesics; 1.6% of the patients were taking pain medication as required, and 7.3% did not receive prior analgesic therapy (no data for four patients). Table 2 shows the immediate analgesic therapy preceding tapentadol PR treatment. Overall 22.1% of all patients received analgesics as required, in the majority of cases in addition to long-term pain therapy. The use of antidepressants (36.4%), antiepileptics (32.1%), laxatives (17.2%) and antiemetics (8.2%) was also documented.
Treatment with tapentadol PR Patients were switched to tapentadol PR mainly owing to insufficient pain relief (84.6%) or insufficient quality of life (63.7%) (multiple responses permitted). Additional reasons were insufficient overall tolerability (26.2%), insufficient balance between effectiveness and tolerability (25.4%), interactions with concomitant medications (4.6%), and a lack of compliance (4.1%). In 73.8% of the patients tapentadol PR treatment was initiated using 2 50 mg/day; 15.8% received an initial dose of 2 100 mg/day and 6.3% of at least 2 150 mg/ day. The mean daily dosage was 131.7 67.1 mg at start of therapy, 204.4 118.4 mg at the end of the titration phase and 227.1 131.2 mg after the 3 month observation. The mean duration of treatment was 81.3 37.1 days for this cohort; 71.1% of the patients continued treatment. At treatment initiation with tapentadol PR 47.8% of the patients still received additional long-term medication (6.5% strong opioids, 3.6% weak opioids, 43% nonopioids; multiple responses permitted); this proportion was reduced to 35.7% (7.4% strong opioids, 2.8% weak opioids, 31.6% non-opioids) at the end of 3 months. Oxycodone/naloxone and oxycodone (both 1.7%) as well as morphine (1.6%) were the most frequently Table 2. Analgesic medication immediately preceding therapy with tapentadol PR (n ¼ 1457). WHO III analgesicsa Oxycodone/naloxone Oxycodone Hydromorphone Buprenorphine Fentanyl (transdermal) Morphine Other Weak opioidsa Tilidine/naloxone Tramadol Other Non-opioidsa Nonsteroidal anti-inflammatory drugs Metamizole Muscle relaxants Other
608 (41.7) 139 (9.5) 129 (8.6) 114 (7.8) 92 (6.3) 91 (6.3) 79 (5.4) 12 (0.8) 507 (34.8) 284 (19.5) 242 (16.6) 2 (0.1) 881 (60.5) 516 (35.4) 245 (16.8) 230 (15.8) 161 (11.1)
Data are number of patients (%). a Multiple responses permitted.
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10 9
Baseline visit
End of observation
8 7
6.8
6.7
6 5
4.4* 3.5*
4 3 2 1 0
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Cohort I (3 months) n=1351
Cohort II (12 months) n=565
Figure 1. Reduction in mean pain intensity under tapentadol PR therapy. Only patients with data for both observation times were included. NRS, 11-point numerical rating scale. *p 0.001 (descriptive) compared to baseline visit (Wilcoxon rank test).
prescribed strong opioids. At end of observation, exclusive long-term analgesic treatment with tapentadol PR was reported for 46.4% of the patients; 9.9% received medication as required in addition to tapentadol PR (no data for 8%). Treatment effects During the 3 month observation period, pain intensity was reduced by 2.4 points to 4.4 2.2 (Figure 1). A total of 38.1% of the patients achieved a pain reduction of at least 50%, and 38.3% attained their pain intensity target of 3.0 1.3 determined at baseline (data for n ¼ 1351). Quality of sleep and quality of life both improved by 2.1 points from 5.8 2.5 to 3.7 2.5, and from 6.5 2 to 4.3 2.4, respectively; impairments in social activities improved by 2.2 points from 6.6 2.4 to 4.4 2.6, independence by 1.7 points from 4.9 2.7 to 3.2 2.5, and libido by 1.2 points from 5.7 3.6 to 4.5 3.4 (all descriptive p 0.001). The most frequently selected additional individual treatment targets derived from the areas of quality of life (69.2%) and physical functioning (46.8%). At end of observation, 75.1% of the patients with data (n ¼ 1314) had achieved their individual treatment target. The combined response rate was 74.3% (data for n ¼ 1361).
Effectiveness analysis cohort II (12 month observation) Demographic and medical history characteristics of this cohort were comparable to cohort I (Table 1). Apart from a slightly lower proportion of patients under longterm metamizole therapy (16.8% vs. 12.9%), there were 2088
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no considerable differences to cohort I regarding immediate long-term medication preceding tapentadol therapy and regarding the reasons for prescribing tapentadol PR. The mean tapentadol PR dose at start of treatment was 130.8 63.8 mg/day, increased slightly more than in cohort I after titration (218.2 119.6 mg/day vs. 204.4 118.4 mg/day), and was 245.8 122.3 mg (229.7 119.3 in cohort I) after 4–6 weeks. Dosages further increased during a mean treatment duration of 348.2 69.4 days by on average 26.8 mg to 272.6 139.5 mg/day. Most patients (80.1%) continued treatment after the 12 month observation period. At end of observation, 45.9% of the patients received long-term monotherapy with tapentadol PR; 15.5% received additional analgesics as required (no data for 6.8%). The proportion of patients requiring additional long-term pain medication decreased to 31.1% (Figure 2). Less patients than in the 3 month cohort were administered additional strong opioids (3.2% vs. 7.4%); most common among those were morphine (1%), oxycodone/naloxone (0.7%) and oxycodone (0.5%). The proportion of patients with antiemetics declined from 17.7% to 4.9% (no data for 7.5%). Pain relief Mean pain intensity was 6.7 1.6 at baseline and was reduced by 3.2 points to 3.5 2.1 over the 12 month observation period (Figure 1). Pain relief was also observed during the daily course over 24 h. Fewer patients suffered from constant pain with pain attacks (34.6% before treatment initiation, 19.7% at end of observation) or intermittent pain attacks with painful intervals (7.3% to 2.4%). The proportion of patients with pain-free intervals increased from 8.2% to 24.3%. Pain relief and tapentadol dosages over the 12 month observation period were also analyzed for patients for whom data for all observation times were available (start of treatment, after 3, 6 and 9 months, and at end of observation) and who continued tapentadol treatment after 12 months (n ¼ 455). Mean pain intensity prior to tapentadol treatment was 6.7 1.6 points. Figure 3 shows a marked reduction in pain intensity during the first 3 months followed by further improvements (overall 3.5 points) under relatively stable tapentadol dosages after dose adjustments. Quality of sleep and quality of life At the end of the 12 month observation all assessed parameters showed marked improvements compared to baseline (Figure 4). Pain-related impairments in quality of life improved as follows: social activities by 3.5 points, quality of life by 3.4 points, quality of sleep by 3.1 points, and independence and libido both by 2.6 points. The frequency of waking up during the night owing to pain also decreased. At baseline, 64.5% of patients reported waking up at least www.cmrojournal.com ! 2014 Informa UK Ltd
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Immediate pretreatment
90
Treatment initiation
80
End of observation
70 59% 60 48%
50 40
45%
42% 36%
32%
29%
30 20 10
4% 3%
4% 3%
0 Non-opioids
Weak opioids
Strong opioids
Figure 2. Long-term analgesics immediately preceding the start of tapentadol treatment and in addition to tapentadol PR during the 12 month observation period (cohort II, n ¼ 588). Multiple responses permitted.
253
9
263
273
275
300 250
8 7 6
6.7
5
129
200 150
4 3.7
3
3.8
3.4
100 3.2
2
50
Mean tapentadol dose (mg/day)
10 Mean pain intensity (NRS 0–10)
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Total
1 0
0 Start
3
6
9
12
Treatment (months)
Figure 3. Tapentadol PR dose stability and reduction of pain intensity during the 12 month observation period (n ¼ 455). Only patients with data for all observation times were included. NRS, 11-point numerical rating scale.
twice during the night whereas this was only reported by 22.3% at end of observation. The proportion of patients with uninterrupted sleep increased from 9.4% to 34.7%.
Treatment success A total of 56.5% of patients had a reduction in pain intensity of at least 50% at end of observation (Figure 5). They had stated a mean pain intensity of 2.93 1.2 as intended treatment target at baseline visit; after 12 months, mean pain intensity was 3.49 2.1. Overall, 54.3% achieved their intended pain reduction. The most frequently selected additional individual treatment targets derived from the areas quality of life (65.3%) and physical functioning (47.5%). At end of observation 88.8% of patients had reached or exceeded their individual treatment target: 15.6% rated ‘much better than expected’, 40.1% ‘better ! 2014 Informa UK Ltd www.cmrojournal.com
than expected’, and 33% ‘as expected’. The combined response rate was 92.3%.
Tolerability In addition to the 1509 patients with case report forms, 28 patients without effectiveness data but ADR documentation were included in the tolerability analysis (n ¼ 1537; safety population). A total of 331 patients (21.5%) experienced 737 ADRs. Of these, 95.9% were not serious and 79% were known for tapentadol PR. The most frequent ADRs (for 410 patients) were nausea (96 patients/6.3%), dizziness (58/3.8%), fatigue (44/2.9%), hyperhidrosis (32/2.1%), vomiting (31/2%), headache (21/1.4%), constipation (20/1.3%), somnolence (20/1.3%), restlessness (19/1.2%), upper abdominal pain (17/1.1%), pruritus (16/1%), diarrhea (15/1%), tremor (13/0.9%), dry mouth (12/0.8%) and sleep disturbances (11/0.7%). Among the 588 patients with 12 month data 94 ADRs were documented for 53 patients (9%). Of these, 97.9% were not serious and 77.7% were known for tapentadol PR. Nausea (9 patients, 1.5%), constipation (7/1.2%), dizziness (6/1.1%), and hyperhidrosis and headache (both 5/0.9%) were most frequent.
Discussion The majority of patients described here already had a long pain duration; 79% of the patients with 12 month data had been suffering for more than 2 years from severe chronic pain. Despite long-term treatment with several, often strong analgesics (42% of patients received WHO III medication) the burden of pain at baseline visit was high Long-term chronic pain treatment with tapentadol PR Strick
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Mean impairment (NRS 0–10)
10 Baseline visit
9
End of observation
8
6
6.7
6.5
7 5.9
5.8 4.9
5 4 3
3.2*
3.1*
2.8*
3.2* 2.3*
2 1 0
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Sleep quality n=531
Quality of life n=538
Social activities n=528
Independence n=523
Libido n=442
Figure 4. Impairment of quality of sleep and quality of life parameters (during the previous 4 weeks) over the 12 month observation period (cohort II). Only patients with data for both observation time points were included. NRS, 11-point numerical rating scale. *p 0.001 (descriptive) compared to baseline visit (Wilcoxon rank test).
At least 50% pain reduction
56.5% (n=565)
Attainment of pain intensity target
54.3% (n=565)
Attainment of additional individual treatment target
88.8% (n=563)
Combined response rate
92.3% (n=586) 0
20 40 60 80 Proportion of patients (%)
100
Figure 5. Proportion of patients who attained one or several therapy targets at the end of the 12 month observation period (cohort II, n ¼ 588). Combined response rate, attainment of intended pain reduction and/or of the additional individual therapy target.
and the main reasons for switching medication were insufficient pain relief and reduced quality of life of the patients. Long-term treatment with tapentadol PR resulted in an effective pain reduction for a broad range of pain diagnoses including nociceptive pain (caused e.g. by gonarthrosis or coxarthrosis), neuropathic pain (e.g. postherpetic neuralgia) or mixed pain (back or tumor pain). After 12 months of treatment 57% of patients had clinically relevant pain relief of at least 50%. Furthermore, additional long-term analgesic treatment was markedly reduced and 46% of patients were exclusively treated with tapentadol PR. The intended mean treatment target of 2.9 points (determined by the patients at baseline on the pain scale) was achieved or exceeded by 54% of patients. Overall, mean pain intensity at end of observation was 0.6 points higher than hoped for. This treatment target was probably too ambitious for this patient population with long pain duration and previous long-term analgesic treatment consisting of often several pain medications. The pain reduction observed here was accomplished without using the maximum permitted tapentadol dosages; 2090
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treatment success might thus be further improved. The mean daily dosage of 273 140 mg after 12 months was markedly lower than the permitted maximum dose of 500 mg/day. These doses were also lower than the ones administered in a randomized clinical safety study which assessed tapentadol long-term therapy for chronic low back or osteoarthritis pain10. In this study, all patients who completed the study received on average 381 102 mg tapentadol PR/day. As in the current observation, a mean pain reduction of 3.2 points was observed. The authors of the safety study could not find any indication for acquired tolerance within the tested dose range in patients treated for a year with tapentadol PR. Following initial dose adjustments during the first 4–6 weeks, there were also only small changes in daily dosages during the 1 year assessment period of this study and tapentadol was associated with reliable pain relief. Severe pain can result in impairments in daily life such as restrictions in social activities and quality of sleep, loss of independence, anxiety, depression and reduced quality of life; these impairments increase with increasing pain www.cmrojournal.com ! 2014 Informa UK Ltd
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chronification11. Restoring or preserving a patient’s autonomy and quality of life is therefore a matter of priority for modern pain management. Treatment with tapentadol PR showed marked improvements in social activities, independence, libido, quality of sleep, and quality of life. A total of 89% of the patients achieved their additional individual treatment target which could be selected from different areas of daily life. The treatment success can also be gauged from the combined response rate: 92% of all patients attained their intended pain reduction and/or their additional individual treatment target. The analysis of the larger patient population (cohort I, n ¼ 1457) showed a level of pain relief over the 3 month observation period which is comparable to randomized clinical studies3. As expected, treatment success for patients consulting a pain specialist was not as high after 3 months as for patients in general practice or patients treated by specialists for internal medicine5. Patients treated by a pain specialist usually had already suffered from severe chronic pain for a long time (77% for more than 2 years compared to 48% in general practice), could not be adequately treated by general practitioners and had still not experienced sufficient pain relief following conservative treatment by the pain specialist with often strong analgesics. Pain relief with tapentadol PR could be further improved in these patients during the next 9 months. Overall, tapentadol PR treatment was well tolerated. Adverse drug reactions were documented for approx. 1/5 (21.5%) of all patients of the entire safety population (n ¼ 1537); 9% of the patients under long-term treatment (12 months; n ¼ 588) were affected. The most frequent side effects were often typical for opioids. Overall, when administering tapentadol, there is, however, a significantly lower risk for typical opioid side effects such as nausea, vomiting, constipation, dizziness, somnolence, and pruritus, as was shown in randomized, controlled comparative studies of tapentadol and oxycodone12–14. The findings from the present daily clinical practice observation regarding tolerability did not lead to changes in the qualitative or quantitative risk profile of tapentadol PR.
Conclusion Pain treatment with tapentadol PR in daily clinical practice resulted in an effective reduction of severe chronic pain also under long-term administration in a broad range of indications accompanied by marked improvements in quality of sleep and quality of life.
Consequences for clinical practice Tapentadol PR can be administered in patients with a long pain duration and thus far insufficient pain relief. ! 2014 Informa UK Ltd www.cmrojournal.com
Volume 30, Number 10
October 2014
Apart from pain control, pain-related impairments in daily life and quality of life can be improved. Tapentadol PR can be administered for a broad range of pain indications. Tapentadol PR is very effective and at the same time well tolerated and can be considered an alternative therapy to classical strong opioids for long-term chronic pain management.
Transparency Declaration of funding This study was supported by Gru¨nenthal GmbH, Aachen, Germany. Declaration of financial/other relationships V.S. has disclosed that he is an advisor for Gru¨nenthal GmbH. He participated in this study and received financial recompense for complete documentation of patients. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments The author thanks all participating physicians, and Elke Grosselindemann and Birgit Brett for writing and editorial assistance. All costs in connection with the preparation of the manuscript were met by Gru¨nenthal GmbH. Previous presentation: Part of the manuscript data was presented in two posters at the German Pain Conference, Hamburg, 23–26 October 2013: Friedrich J, Lehmann U, Schwenke K. Tapentadol PR in daily clinical practice – longterm data from pain specialists (in German). Schmerz 2013;27(Suppl 1):114; Lehmann U, Friedrich J, WaldmannRex S, Schwenke K. Tapentadol PR in daily clinical practice – treatment success in general practice, pain practice and orthopedic practice (in German). Schmerz 2013;27(Suppl 1):114
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