Standard Therapy with Opioids in Chronic Pain ... - Springer Link

ORIGINAL RESEARCH ARTICLE

Clin Drug Invest 2009; 29 Suppl. 1: 17-23 1173-2563/09/0001-0017/$49.95/0 © 2009 Adis Data Information BV. All rights reserved.

Standard Therapy with Opioids in Chronic Pain Management ORTIBER Study Antonio Gatti,1 Carlo Reale,2 Roberto Occhioni,3 Marta Luzi,2 Alessandra Canneti,2 Claudia De Polo,1 Martina Gubernari,1 Massimo Mammucari4 and Alessandro Fabrizio Sabato1 1 2 3 4

University of Tor Vergata, Anaesthesiology and Intensive Care Medicine Department, Rome, Italy University “La Sapienza”, Institute of Anaesthesiology, Resuscitation and Pain Therapy, Rome, Italy Azienda Ospedaliera S. Camillo-Forlanini, Anaesthesiology Department, Rome, Italy Medical Advisor of Anaesthesiology and Intensive Care Medicine Department, University of Tor Vergata, Rome, Italy

Abstract

Objective: Moderate to severe pain is commonly experienced by cancer and noncancer patients. Although opioids are generally the most important drugs in chronic pain management, their use in Italy remains low. We designed a prospective open trial to assess the efficacy and safety of a standard therapy clinically available for a large range of patients. Methods: A total of 172 consecutive patients (89 women and 83 men) with chronic pain (daily mean visual analogue scale (VAS) score > 4) that was not adequately managed by their existing pain regimen were enrolled to receive an immediate release (IR) dose of morphine: 30 mg/day (opioid-naive patients) or 60 mg/day (non-naive patients) for 5 days. After this period (start therapy), all patients were switched to slow release (SR) opioid therapy for 30 days (steady therapy). Each breakthrough pain (BTP) episode was treated with a single dose of IR morphine (20% of the daily dose) during all study periods. Results: Daily VAS score was reduced from 7.4 ± 1.3 at baseline to 3.8 ± 1.5 (p < 0.0001) after 30 days of steady therapy in cancer and non-cancer patients. Fewer patients reported BTP events by study end (55% of patients with BTP at basal time had no BTP at last follow up), and the number of daily BTP events experienced by patients was reduced by therapy to 1–2 per day in 75% of patients reporting BTP. Further, the time delay to reach pain relief following administration of a rescue dose of IR morphine was 15 minutes or less in 52.1% of patients at study end. The standard therapy was well tolerated and fewer adverse effects were recorded at the end of the study period compared with baseline, with the exception of constipation, which showed a moderate increase (from 18.2% to 25.0%). Conclusion: Start therapy with IR morphine followed by conversion to SR opioid therapy could be implemented as a standard therapy to manage moderate to severe

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Gatti et al.

chronic pain in patients with cancer or non-cancer pain. ORamorph® in TIBER study (ORTIBER).

Introduction The management of secondary chronic pain due to degenerative pathologies requires a strong commitment by the healthcare systems of various countries.[1-3] Furthermore, many patients suffer from intense episodic breakthrough pain (BTP) which aggravates the disease, and consequently negatively impacts quality of life.[4] As a result, chronic pain management requires an advanced pharmacological knowledge in order to manage basic therapy and BTP episodes that may occur during the prescribed treatment regimen. Among drugs used to manage chronic pain, opioids have been shown to effectively manage symptoms.[5] However their use in Italy is still very low compared to use in other countries.[6,7] There are numerous reasons for this, but the method by which opioid prescription is regulated, the absolute lack of experience with its short and long-term management, and the patient’s degree of comfort in using opioids, each play fundamental roles. Furthermore, there is widespread and often inappropriate prescription of alternative analgesics such as NSAIDS, despite potential to cause gastric injury.[8] Finally, although international recommendations suggest the use of opioids as a second step in the management of chronic pain,[5] they do not facilitate more extensive use by specialist physicians. Description of a standardized opioid therapeutic approach could facilitate their use and be a useful step forward in the management of degenerative chronic pain. Recently, interesting results have been obtained using a titration dose of immediate release (IR) morphine followed by conversion to a slow release (SR) opioid regimen.[9] Prior examinations of this approach have supported the notion of expanding the use of opioids, as they have indicated the dual benefit of obtaining significant analgesia with a minimal effective dosage.[10,11] In fact, a more extensive use of opioids seems to be a valid solution for treating chronic pain in a great number patients. © 2009 Adis Data Information BV. All rights reserved.

Hence, we sought to evaluate whether a standardized therapy could be used in real clinical settings, especially by those healthcare providers who already use opioids as part of their pain treatment strategies. The objective of this study was to confirm the efficacy and tolerability of opiates administered following a standard therapeutic regimen in patients affected by chronic cancer or non-cancer pain, and whose pain was not being adequately controlled with existing pain relief treatments. The standard therapy included an initial phase (start therapy), involving fixed-dose titration of IR morphine over a period of 5 days, followed by a maintenance period (steady therapy), involving conversion to an SR opioid regimen. ORamorph® in TIBER study (ORTIBER). Patients and Methods This multicentre study involving three different clinical settings enrolled a total of 172 consecutive patients aged ≥18 years with moderate to severe chronic pain (cancer or non-cancer pain). Moderate to severe pain was defined as a daily mean visual analogue (VAS) pain score of >4 on a scale of 0–10, where 10 represents worst pain imaginable. Key exclusion criteria included patients with major contraindications to opioids. The study was conducted in accordance with the Declaration of Helsinki, and in compliance with Good Clinical Practice. The study protocol was approved by each Ethics Committee of the participating centres. All patients provided written consent at the screening. For the start therapy, opioid-naive subjects were treated with IR morphine at a dose of 5 mg every 4 hours per os for 5 days, while non-opioid-naive subjects stopped all previous therapy and were given a similar regimen at a dose of 10 mg every 4 hours. Regular doses were administered at 8 am, 12 noon, 4 pm and 8 pm, and a double dose was administered at 12 midnight to avoid waking the patient at 4 am. In Clin Drug Invest 2009; 29 Suppl. 1

Opioid Therapy for Chronic Pain: ORTIBER

the event of an acute BTP episode during the start therapy phase, patients were allowed to receive one dose of IR morphine per os (20% of cumulative daily dose), when needed. At the end of the 5-day period (start therapy), patients were switched to steady therapy stage with an SR opioid available on the Italian market prescribed at a dose providing an equivalent analgesic benefit. During this phase of steady therapy, subjects were again permitted to have a dose of IR morphine per os when BTP events occurred, at a dose equal to 20% of the opioid dose that had been prescribed for that same day. Follow-up visits were scheduled for 5, 15 and 30 days after initiation of the steady phase (SR opiate therapy). During follow-up visit I, 5 days after initiation of SR therapy, effectiveness and tolerability parameters were evaluated, and the long-term opioid SR therapy was prescribed accordingly. Each patient was re-evaluated for the same effectiveness and tolerability parameters 15 days (follow-up visit II) and 30 days (follow-up visit III) after initiation of SR therapy, and the prescribed therapy was adjusted as needed, and patients were advised to continue taking an IR morphine dose (equal to 20% of daily morphine) to control BTP as required. The primary effectiveness parameters were pain reduction from baseline, the number of BTP episodes per day and the time needed to reach pain relief in incidences of BTP. Pain was measured using a numeric visual analogue scale (VAS; from 0 to 10) administered to the patient by the physician. The VAS score encompassed an assessment of the number of BTP events per day and the number of rescue therapy doses of IR morphine taken. Data entry and statistical analysis was performed and tests were two-sided and evaluated at a significance level of 0.05. The primary aim of the statistical analysis was to compare the level of pain at all follow ups versus pain at basal time. Results The 172 enrolled subjects included 89 women and 83 men, with a mean age of 58.4 ± 11.4 years (from 32yr to 89yr). Of these subjects, 72 presented with cancer pain; 31 an abdominal cancer, 29 a chest © 2009 Adis Data Information BV. All rights reserved.

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cancer and the remaining patients had other cancer location. In the non oncological group osteoarthritis was the main disease (55% of patients). Despite existing pharmacological treatment for pain management, all were still suffering from chronic pain (daily mean VAS pain score > 4). The mean daily VAS pain score at baseline was 7.4 ± 1.3 (range from 4 to 10) and 85 patients (49.4%) were experiencing BTP (44 cancer and 41 non-cancer patients). A substantial proportion (85%) of the subjects were experiencing between three and seven BTP events per day, despite existing pain medication regimens. At baseline, the mean Karnofsky Index (KI) score was 60.8 ± 14.0. Pain medication in the non-cancer subgroup at baseline was: NSAIDs alone, 28.0%; NSAIDs plus tramadol, 26.3%; tramadol alone, 5.1%; and the remaining proportion were taking various other analgesic drugs. In the cancer subgroup, pain medication at baseline was: NSAIDs alone, 9.7%; NSAIDs plus tramadol, 23.6%; transdermal fentanyl, 6.9%; transdermal fentanyl plus NSAIDs 9.7%; and the remaining proportion were taking various other analgesic drugs. On the basis of these therapeutic regimens, patients were subdivided into opiate-naive (n = 113) and non-naive (n = 59) groups for the purposes of defining the starting dose of IR morphine. At baseline, 155 subjects (90.1%) reported adverse effects associated with their existing pain control regime. The most commonly reported adverse effects were; nausea (18.0%), constipation (18.2%), gastric malaise (26.9%), and mental confusion (13.6%). A total of 163 patients completed the study: 9 patients in the cancer group did not show up for follow-up visits I and consequently no data was available for inclusion in the analysis for these patients. Improved pain control was evident at follow-up visit I, 5 days after start therapy with IR opioid treatment, and mean pain scores reduced progressively such that at final follow-up, the mean VAS scores were below 4.0 for both cancer and noncancer pain (figure 1). At the final follow-up visit, Clin Drug Invest 2009; 29 Suppl. 1

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Gatti et al.

VAS score

6 5 4 3 2 1 0 Baseline

Follow-up I* Follow-up II* Follow-up III*

Fig. 1. Mean VAS scores among oncological and non-oncological patients at each follow-up examination. * p < 0.0001 vs basal.

mean VAS scores were significantly lower at all follow up in both, oncological (3.8) and non-oncological (3.9) subjects than at baseline (3.85 ± 1.5 for both groups; p < 0.0001). At the final follow-up, 90% of cancer patients and 55% of non-cancer patients reported a pain reduction of >50%. Regarding therapy history, 63% of opioid-naive subjects and 58% of non-opioidnaive subjects showed a pain reduction greater than 50% (no statistical differences were detected between the two groups). Of those patients who reported BTP, there was a clear and progressive reduction in the number of BTP events reported daily versus baseline (figure 2). Thus, among those patients who reported BTP overall, three-quarters reported one or two daily events at the end of the study versus only 15% at baseline (the remaining 85% reporting between 3 and 7 BTP events per day. The number of patients experiencing BTP events, whether incidental or spontaneous, decreased after steady therapy with SR opioids following the start therapy period in patients with cancer or non-cancer pain (figure 3). Fifty-five percent of overall patients with BTP at basal time had no BTP at the last follow up. Furthermore, there was a trend towards a shorter patient-reported time to pain relief following rescue medication for BTP at follow-up visit III versus follow-up visit I (table I). The opioid treatment regime resulted in a improvement in KI (ns) index in patients with cancer or non-cancer pain, although this improvement was © 2009 Adis Data Information BV. All rights reserved.

less pronounced in patients with cancer pain (table II). At baseline and all follow-up visits, patients reported any adverse drug effects being experienced, and these data are summarized in table III. Effects reported at baseline are attributable to previous pain medication regimens. Overall, there was a marked reduction in the percentage of patients reporting adverse effects at follow-up visit III versus baseline. The incidence of each individual reported adverse event also decreased from baseline, with the exception of constipation, which increased in incidence from 18.2% to 25.0%. Overall, gastric malaise, which was reported by 26.9% of patients at baseline, was not reported by any patients at the third follow-up examination. While 18.1% of patients with cancer pain experia 30

Incident pain Spontaneous pain

25 % of patients with BTP

Cancer pain Non-cancer pain

7

20 15 10 5 0 Follow-up I

Follow-up II

Follow-up III

Follow-up I

Follow-up II

Follow-up III

b 45 40 % of patients with BTP

8

35 30 25 20 15 10 5 0

Fig. 2. Distributions (%) of oncological (a) and non-oncological (b) patients according to the number of BTP events per day at baseline and at each follow-up examination timepoint.

Clin Drug Invest 2009; 29 Suppl. 1


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1–2 events 3–5 events 6–10 events

a 100

% of patients with BTP

90 80 70 60 50 40 30 20 10 0 Baseline

Follow-up I Follow-up II Follow-up III

b 100

% of patients with BTP

90 80 70 60 50 40 30 20 10 0 Baseline

Follow-up I Follow-up II Follow-up III

Fig. 3. Percentage of incidental or spontaneous BTP at each follow-up timepoint among oncological (a) and non-oncological (b) groups.

enced gastric malaise at baseline, none reported it at the first follow-up. Similarly, gastric malaise was reported by 32.0% of non-cancer patients at baseline, with subsequent improvements to 4.0%, 1.1% and 0.0% of patients at follow-up visits I, II and III, respectively.

Discussion Although all the subjects enrolled in this study were already undergoing some form of drug treatment, these treatments provided inadequate pain management and were unable to control BTP in both opioid-naive and non-opioid-naive subjects. The approach of employing a titration dose of IR morphine and subsequent conversion to SR opioids may appear to be a time-consuming process for clinicians, given the closer medical supervision required during the early phase of therapy. However, this approach, as demonstrated here, yields benefits in terms of both efficacy and tolerability.[11] In addition, this approach has also been shown to be useful in conducting opioid rotation.[12-16] In fact, such procedures could become necessary when changing opioids in subjects who show insufficient individual responsiveness, possibly due to a genetically predetermined resistance.[17-19] These data represent an in-practice example because patients often end up consulting a specialist after experimenting unsuccessfully with different regimens. While the standard therapy could be described as an easy, effective and safe method for generally controlling chronic pain, one could argue that a standard therapy does not allow for personalized pain therapy. However, the titration we prescribe during the start therapy phase not only allows a minimum effective dose for each patient to be reached, but also allows for carrying out an opioid rotation with a swift improvement of baseline symptoms. Furthermore, BTP management represents an additional medical imperative,[20] and through the proposed standard therapy, our patients have reported decreased numbers of BTP episodes.

Table I. Time to pain relief after receiving a rescue dose of IR morphine for breakthrough pain Study timepoint

Proportion (%) of patients reporting a response to rescue dose of IR morphine after 5 min

10 min

15 min

20 min

p-Value

25 min

30 min

Follow-up I

0.0

7.0

38.0

39.0

6.0

10.0

p < 0.001a

Follow-up II

1.2

6.1

47.6

32.9

4.9

7.3

p < 0.001a

Follow-up III 2.8 2.8 46.5 36.6 4.2 7.0 p < 0.001a a Chi-square non-parametric test shows that the pain control is more frequent between 5 and 20 minutes and not equally distributed. IR = immediate release.

© 2009 Adis Data Information BV. All rights reserved.


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Gatti et al.

Table II. Karnofsky Index at baseline and follow up visit in cancer and non-cancer patients Karnofsky index

Study timepoint baseline

follow-up I

follow-up II

follow-up III

Oncological

60.42 ± 14.38

63.91a ± 14.06

63.83 ± 16.58

64.0 ± 17.26

Non-oncological

61.63 ± 12.64

68.91a ± 14.94

71.95a ± 16.00

74.86a ± 18.05

a

p < 0.0001.

In this study, the administration of IR morphine per os during the first 5 days of start therapy did not show any significant increases in complications, and individual rescue doses were well tolerated during the entire dosage regimen period. There were higher incidences of adverse events reported at baseline than at the end of the study. The dramatic reduction in incidence of gastric malaise is consistent with the suspension of NSAID use. While the incidence of constipation increased somewhat, this is a common and manageable side effect of opioid use. Together, these data indicate, in a real-world setting, that this approach can facilitate the use of opioid drugs and the management of patients affected by chronic pain. There remain many questions, however, such as the role played by strong opioids when administered to WHO[21] first- and secondstep patients, versus other classes of drugs such as NSAIDs. Our data indicate that adequate pain reduction (50% reduction in pain) was achieved in 48% of non-naive and 63% of naive patients. Further, 90% of cancer pain and 55% of non-cancer pain patients experienced a 50% reduction in pain. These observations suggest that early use of opioid analgesics could achieve better pain control among a wider range of patients relative to other methods. Finally, the duration of the start therapy in this

approach could potentially be reduced from 5 days down to 3 or 4 days in responsive subjects. Conclusion Our data confirm that a standardized opioid therapy approach can be used to manage chronic pain in patients affected by cancer or degenerative pathologies, and further indicate that it is easy and safe to use. The proposed standard therapy (start therapy with IR morphine with subsequent steady therapy with SR opioids, with the use of IR morphine rescue medication at 20% of the daily dose to manage BTP) represents a feasible approach for pain management in patients affected by moderate to severe chronic pain. This pharmacological strategy meets the needs for a personalized therapy because it offers around the clock therapy and a rescue dose (if needed); it also allows for personalized adjustment to a more appropriate dosage of SR opioids. Furthermore, it allows for planning of opioid drug rotation in order to avoid genetically predetermined resistance in some subjects, reducing the adverse effects associated with chronic administration of first-step drugs. Importantly, the test regime was able to reduce the number of BTP events and BTP resolution was commonly achieved within about fifteen min-

Table III. Summary of most common adverse effects reported during the study (% patients) Adverse event

Study timepoint baseline (n = 172)

follow-up I (n = 163)

Nausea

18.0

30.6

4.3

Vomiting

1.8

6.9

1.8

0.0

Constipation

18.2

19.7

28.2

25.0

Mental confusion

13.6

28.9

6.1

3.1

1.8

8.1

3.7

1.2

26.9

23.0

0.6

0.0

Headache Gastric malaise

follow-up II (n = 163)

follow-up III (n = 163) 2.5

Itching

0.6

2.9

2.5

0.0

Other

10.9

22.0

9.2

2.5




utes. Based on these results, supported by a low drop-out rate (5%), we conclude that the standard therapy examined here represents an appropriate pharmacological regimen to manage the initial phase of chronic pain. The therapy also represents a useful tool for re-titrating an ineffective opioid therapy. Acknowledgements This study received no external funding, and the authors have no potential conflicts of interest that are directly relevant. English language assistance for the preparation of this manuscript was provided by Rod McNab, Wolters Kluwer Health Medical Communications. This assistance was funded by Molteni Farmaceutici, Inc. The authors thank Ennio Sarli for data analysis.

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9. De Conno F, Ripamonti C, Fagnoni E, et al. The Merito Study: a multicenter trial of the analgesic effect and tolerability of the normal-release oral morphine during titration phase in patients with cancer pain. Palliat Med 2008; 22 (3): 214–21 10. Mercadante S. Opioid titration in cancer pain: a critical review. Eur J Pain 2007; 11 (8): 823–30 11. Wells N, Murphy B, Douglas S, et al. Establishing the safety and efficacy of an opioid titration protocol. J Opioid Manag 2005; 1 (1): 41–8 12. Bruera E, Pereira J, Watanabe S, et al. Opioid rotation in patients with cancer pain. A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer 1996; 78 (4): 852–7 13. Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer pain. J Clin Oncol 2003; 21 (9 Suppl.): 87s-91s 14. Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer pain. J Clin Oncol 2002; 20 (1): 348–52 15. Portenoy RK. Managing cancer pain poorly responsive to systemic opioid therapy. Oncology (Williston Park) 1999; 13 (5 Suppl. 2): 25-9 16. de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995; 10 (5): 378–84

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Correspondence: Antonio Gatti, University of Tor Vergata, Anaesthesiology and Intensive Care Medicine Department, Rome, Italy. E-mail: [email protected]
