THE QUALITY ASSESSMENT OF ONCOLOGICAL PAIN MANAGEMENT CLINICAL TRIALS IN THE CONTEXT OF A LIMITED NUMBER OF META-ANALYSIS OF OPIOID FORMULATIONS

THE QUALITY ASSESSMENT OF ONCOLOGICAL PAIN MANAGEMENT CLINICAL TRIALS IN THE CONTEXT OF A LIMITED NUMBER OF META-ANALYSIS OF OPIOID FORMULATIONS

W. Giermaziak ^*1, Ż. Bondaryk ², A Markowska ² and T Faluta ³

PhD, Main Medical Library ¹, Chocimska Street 22, 00-791Warsaw, Poland

Main Medical Library ², Chocimska Street 22, 00-791Warsaw, Poland

PhD Student, Military Institute of Medicine ³, Szaserów Street 128, 04-141 Warsaw, Poland

ABSTRACT: Treatment ofcancer painis mainly based on the use of opioidanalgesics.This study includes opioids commonly used in Polish clinical practice, such as: dihydrocodeine, tramadol, buprenorphine, morphine, fentanyl, oxycodone and methadone. The purpose of our research is performing a quality assessment of the available clinical trials concerning opioids efficacy and an evaluation of the cause of the limited quantity of systematic reviews in form of meta-analysis. The quality of methodology used in included trials was assessed by Jadad scale. The following databases was searched: Medline (PubMed), Cochrane Library and websites of agencies included in INAHTA (The International Network of Agencies for Health Technology Assessment in Heath). A wide variety of drug dose, dosage forms, routs of administration and pain measuring scales resulted an impossibility of performing a meta-analysis comparing opioids in terms of their effectiveness. Collected studies were assessed for analgesic effect and side effects of opioids therapeutic use, refer to other drugs and depending on doses, frequency of administration, dosage forms (modified/immediate release). The analysis of safety was performed by evaluating the drug-related side effects that resulted an exclusion from the study and general adverse reactions associated with treatment.

Opioids, Analgesia, Morphine, Oncological Pain, Meta-Analysis

INTRODUCTION: The range of the evidence-based researches concerning effectiveness of opioid analgesia used in oncological pain treatment isn't raising doubts. However, we have to take note of deficiency of wide systematic reviews assessing hierarchies of the effectiveness of opioids taking the methodology of meta-analysis into account. A quality assessment of the available clinical research concerning opioid analgesics efficacy and an evaluation of the cause of the limited quantity of systematic reviews in meta-analysis form are the purpose of this study.

MATERIALS AND METHODS:

A study includes opioids commonly used in Polish clinical practice, such as: dihydrocodeine, tramadol, buprenorphine, morphine, fentanyl, oxycodone and methadone.

For the systematic review of literature following researches were chosen: retrospective, prospective, randomized clinical controlled trials, single/double-blind trials or open-label trials. In the analyzed problem individual opioids, opioids from the same group but varies routes of administration or placebo were used as comparators.

Studies were excluded due to following reasons: theoretical or review type of the publication, too small number of participants (sample size ≤ 10) and also researches focused on mechanisms of disease or mechanisms of the treatment drop-outed of the study. The main endpoint of the study is a grade of the analgesic effect of opioids used in neoplasm pain management.

A selection of information was based on a detailed protocol developed before searching and data compilation. Independently of each other, two researchers searched databases and selected the data. The protocol assumed, that in case of the inconsistency between researchers, there will be a discussion all the way to reaching an agreement.

The quality of methodology used in included trials was assessed by Jadad scale. Additionally, the studies were evaluated for the size of the study groups.

The following databases was searched:

• Medline (PubMed)
• Cochrane Library
• Websites of agencies included in INAHTA (The International Network of Agencies for Health Technology Assessment in Heath).

Additionally, researchers used references found in primary and secondary researches. 257 studies were identified, whose full texts were evaluated according to criteria of inclusion or exclusion from the systematic review. A diagram, according to QUOROM, presents the successive stages of searching and selection of primary and secondary research (Fig.1). Finally, for the systematic review of clinical trials included 72 publications.

RESULTS: The evaluation of endpoints of compared intervention was based on assessment of analgesic effect of opioids. A wide variety of drug dose, dosage forms, routs of administration and pain measuring scales before/after opioids administration, resulted an impossibility of performing a meta-analysis comparing opioids in terms of their effectiveness. The results of overview are captured in Table 1. The study received a high rate of quality on Jadad scale, from 2to 5 points, with the arithmetic mean of 4, 1 points. The results for morphine trials are captured in Table 2

TABLE 1: THE SUMMARY OF THESCALESOF PAIN MEASURED IN PATIENTS TAKING OPIOIDS INCLUDED IN THE REPORT, ORPLACEBO.

TABLE 2: THE QUALITY ASSESSMENT OF INCLUDED PRIMARY TRIALS ABOUT MORPHINE, ACCORDING TO JADAD SCALE.

2* a blinde method was not used

Primary researches about morphine:

Collected studies were assessed for analgesic effect and side effects only in case of morphine therapeutic use, refer to other drugs and depending on doses, frequency of administration, dosage forms (modified/immediate release). According to these criteria, ¹⁹ researches were included. Two of these studies compared morphine admistered orally with modiefied release (MR) and immediate release (IR) ^{4, 9}. Thirwell ⁴ in study focused on immediate released mophine in concentrated form. In five studies, researches considered the pharmacological action of morphine admistered orally MR, depending on the frequency of administration: every 12 hours versus every 24 hours – 3 studies ^{15, 16, 17}, every 8 hours versus every 24 hours – 1 study¹, every 4 hours versus every 24 hours – 1 study². Another group consists of studies evaluating the effects of morphine MR depending on different power. We included studies which compared following doses: 15mg versus 30mg ¹¹, 100mg versus 3x30mg³, 100 mg versus 200 mg ⁸. One of studies evaluated efficacy of morphine admistered orally efficacy depending on time of day – morning / evening ¹⁸. Three studies ^{5, 10, 14} compared morphine administered orally versus rectally, which the last two studies took into account modified release forms. One of studies assessed the efficacy of morphine administered orally in form of mouth washes ⁷. Four included studies compared drug administration routes: - morphine administrated orally (p.o.) versus morphine administered epidurally versus morphine administrated epidurally with catheter ¹⁹; morphine administered intravenously in bolus (i.v). versus intravenous infusion ⁶; - morphine MR administered rectally versus morphine administered subcutaneously (s.c.) ¹². The last study ¹³ compared morphine IR administered intravenously with morphine IR administered subcutaneously. These data were summarized in Table 3.

TABLE 3: MORPHINE -SUMMARY OFCOMPARED INTERVENTIONS FROM PRIMARY RESEARCH.

The analgesic effect was most often measured by VAS scale, which was used in 11 of the 19 studies. In other works, the following scales was used: CAT ³, PPI ⁴, 10-points NRS ¹ and 11-points NRS ¹¹; BS – 11-points ¹⁵. In Carchetti study 7, researchers measured the time required to achieve analgesic effect defined as good or complete. Table 4 shows the types of intervention and types of morphine analgesic effect assessment scales used in the studies. With these data, it appears that due to the diversity of research and applied scales we can nonperformer meta-analysis.

TABLE 4: MORPHINE - THE SUMMARY OF TYPE OF INTERVENTIONS AND ANALGESIC EFFECT SCALE (PAIN SCALE) USED IN STUDIES.

Primary research about oxycodone:

This group included eight studies considered oxycodone administered orally. Two studies ^20-21 compared modified release oxycodone administered every twelve hours and the immediate released oxycodone.  In the remaining six studies ^22-27 researchers evaluated the analgesic efficacy of oxycodone modified release in comparison to modified release morphine. Two studies ^26-27 described oxycodone and morphine administered every 12 hours. Table 5 presents the summary of these studies.

TABLE 5: OXYCODONE - THE SUMMARY OF TYPE OF INTERVENTIONS.

In the group which compares oxycodone CR versus oxycodone IR, visual rating scale (VRS) ²⁰ and other 5 – points unspecified scale ²¹ were used. The second group was less variety in terms of scale which were used. In three researches ^{22, 24, 25} the VAS scale was used. In Bruera study ²⁷, the intensity of pain was measured by both, VAS and CAT scale. Researchers Heiskanen&Kalso²³ used 4 – points VRS scale, Mucci-LoRusso ²⁶ measured pain by CAT scale. Table 5 presents the summary of type of interventions and analgesic effect scale used in studies.

TABLE 6: OXYCODONE – THE SUMMARY OF TYPE OF INTERVENTIONS AND ANALGESIC EFFECT SCALE (PAIN SCALE) USED IN STUDIES

Uniformity of interventions could indicate that implementation of meta-analysis is possible, however, due to the diversity of scales which were used (type, sample size) to measure the effectiveness of analgesic effect, meta-analysis is not possible to perform. Primary research about methadone: This group included three studies ^28-30 which present methadone efficacy in comparison to morphine effectiveness. In Grochow study ²⁸, researcher compared methadone and morphine administered intravenously. Two other studies presented methadone and morphine administered orally: morphine SR ²⁹, morphine IR ³⁰. Table 7 below presents the summary of these studies.

TABLE 7: METHADONE - THE SUMMARY OF TYPE OF INTERVENTIONS.

In each research, analgesic effect was measured by different scale: Grochow ²⁸ - PII (MC Gill Pain Questionnaire), Mercadante ²⁹ – VAS scale, Bruera ³⁰ – differences in the elimination of pain. Table 8 presents the summary of type of interventions and analgesic effect scale used in studies with methadone.

TABLE 8: METHADONE - THE SUMMARY OF TYPE OF INTERVENTIONS AND ANALGESIC EFFECT SCALE (PAIN SCALE) USED IN STUDIES.

The data summared in Table 8 show that meta-analysis is not possible to carry out, due to the diversity of scales which were used to measure the effectiveness of analgesic effect: scale, no scale, type of scale. Primary research about buprenorphine in the buprenorphine group two researches were included: first which compares buprenorphine admistered cutaneously versus placebo ³¹ and second which compares buprenorphine admistered epidurally versus morphine administered epidurally ³². Table 9 presents the summary of these studies.

TABLE9: BUPRENORPHINE – THE SUMMARY BASED ON COMPARED INTERVENTIONS.

 In both studies, analgesic effect was measured by NRS scale. Table 10 presents the summary of type of interventions and analgesic effect scale used in studies with buprenorphine.

TABLE10: THE SUMMARY OF TYPE OF INTERVENTIONS AND ANALGESIC EFFECT SCALE (PAIN SCALE) USED IN STUDIES.

Although using the same scales in both studies, a meta-analysis is not possible to perform, due to the diversity of forms of buprenorphine and comparators.

Primary researches about fentanyl: This group included twenty primary trials ^33-52. Five publications concerned basic oncological pain management ^33-37, and fifteen of them focused on breakthrough pain ^38-52. Among the analyzed publication, three of them compared fentanyl administered transdermally and modified release  (SR) morphine administered orally 35-37. Allthese studies refered basic pain. The Kongsgaard study34 compared fentanyl administered transdermally withplacebo in the treatment of basic pain. The following publications concentrated on analysis of OTFC – oral transmucosal fentanyl citrate – Coluzzi ³⁸, in comparison to immediate-related morphine administered orally – Mercadante ³⁹, morphine administered intravenously – Portenoy ⁴⁰, other different opioids (MOR, OKS and other) and also with placebo - Farrar ⁴¹.

The three researches considered the difference in efficacy and safety between fentanyl buccal tablet (FBT) and placebo ^42-44. A fentanyl pectin nasal spray (FPNS) was compared to modified release morphine administered orally ^45-46, as well as placebo^47-48.

An individual studies described intranasal fentanyl spray (INFS) in comparison to oral transmucosal fentanyl citrate (OTFC) ⁴⁹ or placebo ⁵⁰.

In two studies ^51-52 researched fentanyl buccal soluble film (FBSF) analgetic effectiveness and safety in terms of a placebo. Slatk in ⁴³ compiled fentanyl buccal tablet (FBT) and placebo. One research contained a comparison of subcutaneous fentanyl with morphine subcutaneously administered ³³. Table 11 contains these data.

TABLE 11: FENTANYL - SUMMARY OF INTERVENTION COMPARED IN THE ORIGINAL RESEARCH.

An analgesic effect was measured mostly in 11-degree NRS scale (used it in 15 trials), in three publications a VAS scale was used ^{34, 37, 52}. In other researches this effect was measured by following scales: MAUC ³⁶ and a 10-degree NRS scale ⁴¹. Table 12 presents all types of intervention for fentanyl and types of scales used to evaluate analgesic effect, which was analysed in this report. The following data shows that despite of similar scales used to measure an analgesic effect of opioid, its comparators were different, which made it impossible to perform a meta-analysis.

TABLE 12: FENTANYL - SUMMARY OF THE TYPE OF INTERVENTIONS AND THE SCALE OF ANALGESIC EFFECT ASSESSMENT.

Primary researches about tramadol:

According to inclusion criteria, four studies assessing tramadol analgesic effect in neoplasms patients, were included Table 13. Two studies compare tramadol and morphine, both administered orally ^53-54. One study ⁵⁵ evaluated efficacy of treatment using tramadol modified release and dihydrocodeine. One study ⁵⁶ compared following interventions: oral dose of immediate and slow release tramadol.

TABLE 13: TRAMADOL – THE SUMMARY OF TYPE OF INTERVENTIONS.

The table below presents different type of scales used to measure analgesic effect of opioids. A VAS scale was used in two studies ^54-55, which presented various formulations of tramadol. A Wilder-Smith research ⁵³ measured effectiveness of opioids by VRS scale while Mercadante ⁵⁶ use 11-points NRS scale. Table 14 presents the summary of type of interventions and analgesic effect scale used in studies with tramadol.

TABLE 14: TRAMADOL - THE SUMMARY OF TYPE OF INTERVENTIONS AND ANALGETIC EFFECT SCALE (PAIN SCALE) USEDIN STUDIES.

Due to variety of tramadol dosage forms as well as differences of analgesic effect scale type,

a meta-analysis was not feasible.

An assessment of drug safety: The analysis of safety was performed by evaluating the drug-related side effects that resulted an exclusion from the study and general adverse reactions associated with treatment. These studies led to development general profile of typical side effects of opioids such as:

• constipation
• nausea
• vomiting
• dizziness
• somnolence
• sweating
• dementia
• weakness
• confusion

The highest percentage of patients excluded on account of adverse effect was observed in group using tramadol – 23% and the lowest percentage in group where buprenorphine was used – 1%. Those available results came from small populations (including 107 patients - buprenorphine and 70 patients - tramadol). In the case of morphine, fentanyl and oxycodone - opioids with the largest sample size, the percentage of patients excluded due to side effects developed as follows: 8% - fentanyl, 4% - morphine, 9% - oxycodone. All the results are illustrated in the Fig. 2.

TABLE 15: THE MOST COMMON SIDE EFFECTS REPORTED DURING TRIALS, THE NUMBER OF PATIENTS EXCLUDED DUE TO SIDE EFFECTS

* Laurettiresearch ²⁵ excluded because of no information, of which group the patient was excluded(OKS or MOR)

** Wilde- Smith research ⁵³ excluded because of no informations, of which group the patient was excluded (TRAS or MOR)

FIG.2: SIDE EFFECTS OF OPIOIDS – PERCENTAGE OF EXCLUSION FOR INDIVIDUAL OPIOIDS.

DISCUSSION: Identified primary studies provide high-quality data. An average rating on Jadad scale is as follows: morphine-3.95; oxycodone-3,38; fentanyl-3.45; methadone-3.33; buprenorphine-3.5

and tramadol-3. While the average for all primary publications achieves 3,43. The main limitation of the study is the fact that searching was carried out without access to the Embase database, which resulted a limited number of research involved.
Another limitation is the availability of "head to head" type of research for all analyzed opioids. A morphine is the most commonly used analgetics according to the WHO, and so there are a lot of trials which evaluate its effectiveness in comparison to oxycodone, methadone, fentanyl and tramadol.

Beyond that, even within the group of opiods, there was a wide variety of forms of drug administration. It should also be noted – a various time of analgesic effect intervals (a daily average, an average after stable analgesic effect achievement) and the diversity of pain intensity scales. This had a direct impact on the inability to perform a meta-analysis.

Another limitation is the sizeof population related to the results for various opioids. The smallest number of patients was involved in studies about buprenorphine, methadone and tramadol (less than 250 people for each opioid). Researches about oxycodone included more than 400 patients, about morphine over 800, and fentanyl just over 1900.

In addition to the above, more restrictions which could have a significant impact on the study results, have not been identified.

CONCLUSIONS: The analysis of clinical trials evaluating the efficacy of opioids used in oncological pain treatment is a high-quality research by Jadad scale. They are mostly clinical controlledtrials, with a randomization and single/double-blind method.

The study includes opioids commonly used in the Polish clinical practice, such as: tramadol, buprenorphine, morphine, fentanyl, oxycodone and methadone. An individual studies suggest the effectiveness of various opioids, however, different types of  pain intensity assessment scales and the diversity of the studies groups make it impossible to present the meta-analysis. This is probably the main reason for which the number of systematic reviews, especially with a meta-analysis is limited for this therapy. This research confirms the inability to perform a meta-analysis on the basis of the available primary studies, because of important differences in drug dosage, doses and pain assessment scales.

REFERENCES:

4. Mignault GG, Latreille J, Viguié F, Richer P, Lemire F, Harsanyi Z, Stewart JH, Control of cancer-related pain with MS Contin: a comparison between 12-hourly and 8-hourly administration. J Pain Symptom Manage. 1995; 10, 6: 416-22
5. Goughnour BR, Arkinstall WW, Stewart JH. Analgesic response to single and multiple doses of controlled-release morphine tablets and morphine oral solution in cancer patients. Cancer. 1989; 1, 63 (11 Suppl): 2294-7.
6. Portenoy RK, Maldonado M, Fitzmartin R, Kaiko RF, Kanner R, Oral controlled-release morphine sulfate. Analgesic efficacy and side effects of a 100-mg tablet in cancer pain patients. Cancer. 1989;1, 63 (11 Suppl): 2284-8.
7. Thirlwell MP, Sloan PA, Maroun JA, Boos GJ, Besner JG, Stewart JH, Mount BM, Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. 1989; 1, 63 (11 Suppl): 2275-83.
8. Moolenaar F, Meijler WJ, Frijlink HW, Visser J, Proost JH, Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain. Eur J ClinPharmacol. 2000; 56, 3: 219-23.
9. Gourlay GK, Plummer JL, Cherry DA, Onley MM, Parish KA, Wood MM, Cousins MJ, Comparison of intermittent bolus with continuous infusion of epidural morphine in the treatment of severe cancer pain. 1991; 47 (2): 135-40.
10. Cerchietti LC, Navigante AH, Körte MW, Cohen AM, Quiroga PN, Villaamil EC, Bonomi MR, Roth BM, Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. 2003;105 (1-2): 265-73
11. Hanks GW, Hanna M, Finlay I, Radstone DJ, Keeble T, Efficacy and pharmacokinetics of a new controlled-release morphine sulfate 200-mg tablet. J Pain Symptom Manage. 1995;10 (1): 6-12.
12. Klepstad P, Kaasa S, Jystad A, Hval B, Borchgrevink PC, Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: a randomized, double-blind trial. 2003;101 (1-2): 193-8
13. De Conno F, Ripamonti C, Saita L, MacEachern T, Hanson J, Bruera E., Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. J ClinOncol. 1995;13 (4): 1004-8.
14. Ridgway D, Sopata M, Burneckis A, Jespersen L, Andersen C, Clinical efficacy and safety of once-daily dosing of a novel, prolonged-release oral morphine tablet compared with twice-daily dosing of a standard controlled-release morphine tablet in patients with cancer pain: a randomized, double-blind, exploratory crossover study. J Pain Symptom Manage. 2010; 39 (4): 712-20.
15. Bruera E, Fainsinger R, Spachynski K, Babul N, Harsanyi Z, Darke AC, Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J ClinOncol. 1995; 13 (6): 1520-7.
16. Elsner F, Radbruch L, Loick G, Gaertner J, Sabatowski R, Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain. J Palliat Med. 2005; 8 (4): 743-50.
17. Babul N, Provencher L, Laberge F, Harsanyi Z, Moulin D, Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain. J ClinPharmacol. 1998; 38 (1): 74-81.
18. O'Brien T, Mortimer PG, McDonald CJ, Miller AJ, A randomized crossover study comparing the efficacy and tolerability of a novel once-daily morphine preparation (MXL capsules) with MST Continus tablets in cancer patients with severe pain. Palliat Med. 1997; 11 (6): 475-82.
19. Hagen NA, Thirlwell M, Eisenhoffer J, Quigley P, Harsanyi Z, Darke A, Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain. J Pain Symptom Manage. 2005; 29 (1): 80-90.
20. Broomhead A, Kerr R, Tester W, O'Meara P, Maccarrone C, Bowles R, Hodsman P, Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain. J Pain Symptom Manage. 1997; 14 (2): 63-73.
21. Currow DC, Plummer JL, Cooney NJ, Gorman D, Glare PA, A randomized, double-blind, multi-site, crossover, placebo-controlled equivalence study of morning versus evening once-daily sustained-release morphine sulfate in people with pain from advanced cancer. J Pain Symptom Manage. 2007; 34 (1): 17-23.
22. Vainio A, Tigerstedt I., Opioid treatment for radiating cancer pain: oral administration vs. epidural techniques. ActaAnaesthesiol Scand. 1988; 32 (3): 179-85.
23. Kaplan R¹, Parris WC, Citron ML, Zhukovsky D, Reder RF, Buckley BJ, Kaiko RF, Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain. J ClinOncol. 1998; 16 (10): 3230-7.
24. Stambaugh JE, Reder RF, Stambaugh MD, Stambaugh H, Davis M, Double-blind, randomized comparison of the analgesic and pharmacokinetic profiles of controlled- and immediate-release oral oxycodone in cancer pain patients. J ClinPharmacol. 2001; 41 (5): 500-6.
25. Heiskanen TE, Ruismäki PM, Seppälä TA, Kalso EA, Morphine or oxycodone in cancer pain? 2000; 39 (8): 941-7
26. Heiskanen T, Kalso E, Controlled-release oxycodone and morphine in cancer related pain. 1997; 73 (1): 37-45.
27. Kalso E, Vainio A, Morphine and oxycodone hydrochloride in the management of cancer pain. 1990; 47 (5): 639-46.
28. Lauretti GR, Oliveira GM, Pereira NL. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003; 1, 89 (11): 2027–2030.
29. Mucci-LoRusso P, Berman BS, Silberstein PT, Citron ML, Bressler L, Weinstein SM, Kaiko RF, Buckley BJ, Reder RF, Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study. Eur J Pain. 1998; 2 (3): 239-49.
30. Bruera E, Belzile M, Pituskin E, Fainsinger R, Darke A, Harsanyi Z, Babul N, Ford I, Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. J ClinOncol. 1998; 16 (10): 3222-9.
31. Grochow L, Sheidler V, Grossman S, Green L, Enterline J, Does intravenous methadone provide longer lasting analgesia than intravenous morphine? A randomized, double-blind study. 1989; 38 (2): 151-7.
32. Mercadante S, Casuccio A, Agnello A, Serretta R, Calderone L, Barresi L, Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home. J ClinOncol. 1998; 16 (11): 3656-61.
33. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, Strasser F, Willey J, Bertolino M, Mathias C, Spruyt O, Fisch MJ, Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J ClinOncol. 2004; 1, 22 (1): 185-92.
34. Poulain P, Denier W, Douma J, Hoerauf K, Samija M, Sopata M, Wolfram G, Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain. J Pain Symptom Manage. 2008; 36 (2): 117-25.
35. Pasqualucci V, Tantucci C, Paoletti F, Dottorini ML, Bifarini G, Belfiori R, Berioli MB, Grassi V, Sorbini CA., Buprenorphine vs. morphine via the epidural route: a controlled comparative clinical study of respiratory effects and analgesic activity. 1987; 29 (3): 273-86.
36. Hunt R, Fazekas B, Thorne D, Brooksbank M, A comparison of subcutaneous morphine and fentanyl in hospice cancer patients. J Pain Symptom Manage. 1999 Aug; 18 (2): 111-9.
37. Kongsgaard UE, Poulain P. Transdermal fentanyl for pain control in adults with chronic cancer pain. Eur J Pain. 1998; 2 (1): 53-62.
38. Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Verna L, Villari P, Ficorella C, Gebbia V, Riina S, Casuccio A, Mangione S, Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. Eur J Pain. 2008; 12 (8): 1040-6.
39. van Seventer R, Smit JM, Schipper RM, Wicks MA, Zuurmond WW, Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin. 2003; 19 (6): 457-69.
40. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage. 1997; 13 (5): 254-61.
41. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, Chavez J, Ashley J, Lebo D, McCracken M, Portenoy RK, Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). 2001; 91 (1-2): 123-30.
42. Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G, Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer. 2007; 18, 96 (12): 1828-33
43. Portenoy RK, Payne R, Coluzzi P, Raschko JW, Lyss A, Busch MA, Frigerio V, Ingham J, Loseth DB, Nordbrock E, Rhiner M, Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. 1999; 79 (2-3): 303-12.
44. Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E, Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst. 1998; 15, 90 (8): 611-6.
45. Portenoy RK, Taylor D, Messina J, Tremmel L, A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006; 22 (9): 805-11.
46. Slatkin NE, Xie F, Messina J, Segal TJ, Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol. 2007; 5(7): 327-3
47. Zeppetella G, Messina J, Xie F, Slatkin NE, Consistent and clinically relevant effects with fentanyl buccal tablet in the treatment of patients receiving maintenance opioid therapy and experiencing cancer-related breakthrough pain. Pain Pract. 2010; 10 (4): 287-93.
48. Fallon M, Reale C, Davies A, Lux AE, Kumar K, Stachowiak A, Galvez R; Fentanyl Nasal Spray Study 044 Investigators Group, Efficacy and safety of fentanyl pectin nasal spray compared with immediate-release morphine sulfate tablets in the treatment of breakthrough cancer pain: a multicenter, randomized, controlled, double-blind, double-dummy multiple-crossover study. J Support Oncol. 2011; 9 (6): 224-31.
49. Davies A, Sitte T, Elsner F, Reale C, Espinosa J, Brooks D, Fallon M, Consistency of efficacy, patient acceptability, and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulfate in breakthrough cancer pain. J Pain Symptom Manage. 2011; 41 (2): 358-66
50. Portenoy RK, Burton AW, Gabrail N, Taylor D, A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain. 2010; 151 (3): 617-24.

48. Taylor D, Galan V, Weinstein SM, Reyes E, Pupo-Araya AR, Rauck R; Fentanyl Pectin Nasal Spray 043 Study Group, Fentanyl pectin nasal spray in breakthrough cancer pain. J Support Oncol.2010; 8 (4): 184-90.
49. Mercadante S, Radbruch L, Davies A, Poulain P, Sitte T, Perkins P, Colberg T, Camba MA, A comparison of intranasal fentanyl spray with oral transmucosalfentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial. Curr Med Res Opin. 2009; 25 (11): 2805-15.
50. Kress HG, Orońska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T, Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. 2009; 31 (6): 1177-91.
51. Rauck R, North J, Gever LN, Tagarro I, Finn AL, Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized, double-blind, placebo-controlled study. Ann Oncol. 2010; 21 (6): 1308-14.
52. Lennernäs B, Frank-Lissbrant I, Lennernäs H, Kälkner KM, Derrick R, Howell J, Sublingual administration of fentanyl to cancer patients is an effective treatment for breakthrough pain: results from a randomized phase II study. Palliat Med. 2010; 24 (3): 286-93.
53. Wilder-Smith CH, Schimke J, Osterwalder B, Senn HJ, Oral tramadol, a mu-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol. 1994; 5 (2): 141-6.
54. Leppert W. Analgesic efficacy and side effects of oral tramadol and morphine administered orally in the treatment of cancer pain. Nowotwory. 2001; 51, 3: 257-266.
55. Leppert W, Majkowicz M. The impact of tramadol and dihydrocodeine treatment on quality of life of patients with cancer pain. Int J ClinPract. 2010; 64 (12): 1681-7.

56. Mercadante S, Arcuri E, Fusco F, Tirelli W, Villari P, Bussolino C, Campa T, De Conno F, Ripamonti C. Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain. 2005; 13 (9): 702-7.
    

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    How to cite this article:

    Giermaziak W, Bondaryk Ż., Markowska A and Faluta T: The Quality Assessment of Oncological Pain Management Clinical Trials in the Context of a Limited Number of Meta-Analysis of Opioid Formulations. Int J Pharm Sci Res 2015; 6(8): 3412-23.doi: 10.13040/IJPSR.0975-8232.6(8).3412-23.

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