Opioid Therapy for Cancer-Related Pain - Donau-Universit¤t Krems

Opioid Therapy for Cancer-Related Pain A Systematic Review of the Comparative Efficacy, Effectiveness and

Risk of Harms of Extended-Release Opioids

October 2012

Department for Evidence-based Medicine and Clinical Epidemiology

Authors

Ursula Griebler, PhD, MPH

Anna Glechner, MD

Christina Kien, MSc

Michaela Strobelberger, MA

Bita Mesgarpour PharmD, MPH

Megan G. Van Noord, MSIS

Andrea Michalek-Sauberer, MD

External Reviewers

Engelbert Deusch, MD

Gerald Gartlehner, MD, MPH

Kylie Thaler, MD, MPH

Ekkehard Schweitzer,MD, DEAA

Funding Source

This review was funded by Grünenthal GmBH

Imprint

Danube University Krems

Department for Evidence-based Medicine and Clinical Epidemiology

Dr.-Karl-Dorrek-Straße 30

3500 Krems an der Donau, Austria

Table of Contents 1 Executive Summary ........................................................................................................................................ 1

1.1 Background ............................................................................................................................................ 1

1.2 Methods ................................................................................................................................................ 2

1.3 Results ................................................................................................................................................... 4

1.4 Discussion .............................................................................................................................................. 5

2 Introduction.................................................................................................................................................... 6

2.1 Background ............................................................................................................................................ 6

2.1.1 Cancer Pain ........................................................................................................................................ 6

2.1.2 Treatment Strategies (Opioids) ......................................................................................................... 8

2.1.3 Pharmacology of Analgesic Opioids ................................................................................................ 10

2.2 Scope and Key Questions .................................................................................................................... 17

3 Methods ....................................................................................................................................................... 19

3.1 Topic Refinement and Review Protocol .............................................................................................. 19

3.2 Search Strategy .................................................................................................................................... 19

3.3 Eligibility Criteria .................................................................................................................................. 20

3.3.1 Population ....................................................................................................................................... 20

3.3.2 Intervention..................................................................................................................................... 20

3.3.3 Control ............................................................................................................................................. 21

3.3.4 Outcomes ........................................................................................................................................ 21

3.3.5 Timing .............................................................................................................................................. 22

3.3.6 Setting ............................................................................................................................................. 22

3.4 Study Selection .................................................................................................................................... 22

3.5 Data Extraction .................................................................................................................................... 23

3.6 Risk of Bias Assessment of Individual Studies ..................................................................................... 23

3.7 Data Synthesis ..................................................................................................................................... 24

3.8 Strength of Body of Evidence .............................................................................................................. 24

4 Results .......................................................................................................................................................... 26

4.1 Introduction ......................................................................................................................................... 26

4.2 Results of Literature Searches ............................................................................................................. 26

4.3 Description of Included Studies ........................................................................................................... 27

4.4 Key Question 1: Comparative Efficacy and Effectiveness of Extended-Release Opioids ..................... 28

4.4.1 Description of Included Studies ...................................................................................................... 28

4.4.2 Key Points ........................................................................................................................................ 30

4.4.3 Detailed Synthesis ........................................................................................................................... 30

4.5 Key Question 2: Comparative Risk of Harms of Extended-Release Opioids ........................................ 42

4.5.1 Description of Included Studies ...................................................................................................... 42

4.5.2 Key Points ........................................................................................................................................ 45

4.5.3 Detailed Synthesis ........................................................................................................................... 46

4.5.3.1.2 Comparative Risk of Serious Adverse Events .......................................................................... 50

4.6 Key Question 3: Efficacy, Effectiveness, or Risk for Harms in Subpopulations .................................... 83

5 Discussion ..................................................................................................................................................... 84

5.1 Key Findings and Strength of Evidence ................................................................................................ 84

5.2 Gaps in the Evidence ........................................................................................................................... 85

6 Conclusions................................................................................................................................................... 86

7 References .................................................................................................................................................... 87

8 Appendices ................................................................................................................................................... 90

List of Tables Table 1: Extended-Release Opioid Analgesic Products. ........................................................................................ 11 Table 2: Extended-Release Opioids Approved for Treatment of Moderate to Severe Pain in Austria

1,

Switzerland2, Germany

3, UK

4, and US

5. ................................................................................................................. 12

Table 3: Included Drugs and Combination of Drugs.............................................................................................. 21 Table 4: Outcomes and Eligibility Criteria. ............................................................................................................ 22 Table 5: Definitions of the Grades of the Overall Quality of Evidence. ................................................................ 25 Table 6: Outcomes Viewed as Critical or Important for Decision-Making. ........................................................... 25 Table 7: Characteristics of the Available Evidence for KQ1. ................................................................................. 29 Table 8: Risk of Bias Summary for RCTs Included for KQ1. ................................................................................... 29 Table 9: Study Characteristics for all Studies Included for KQ1, the Investigated Outcomes and Risk of Bias Ratings. .................................................................................................................................................................. 31 Table 10: Study Characteristics and Summary of Findings on Pain Intensity. ...................................................... 35 Table 11: Study Characteristics and Summary of Findings on Quality Of Life. ..................................................... 38 Table 12: Study Characteristics and Summary of Findings on Functional Capacity. ............................................. 39 Table 13: Study Characteristics and Summary of Findings on Patient Perceived Effectiveness. .......................... 40 Table 14: Study Characteristics and Summary of Findings on Cognitive Performance......................................... 41 Table 15: Rates of Discontinuation Due to Lack of Efficacy by Study Drug. .......................................................... 41 Table 16: Characteristics of the Available Evidence for KQ2. ............................................................................... 43 Table 17: Risk of Bias Summaries for RCTs Included for KQ2................................................................................ 44 Table 18: Risk of Bias Summary for Observational Studies Included for KQ2. ...................................................... 44 Table 19: Study Characteristics for all Studies Included for KQ2, the Investigated Outcomes and Risk of Bias Ratings. .................................................................................................................................................................. 47 Table 20: Reported Frequencies of Serious Adverse Events by Drug. .................................................................. 50 Table 21: Study Characteristics and Summary of Findings on Serious Adverse Events. ....................................... 54 Table 22: Drop-Out Rates and Risk for Specific Adverse Events During the Stable Phase of Treatment.............. 57 Table 23: Study Characteristics and Summary of Findings of Constipation. ......................................................... 62 Table 24: Study Characteristics and Summary of Findings o Nausea and Vomiting. ............................................ 72 Table 25: Studies Assessing Dizziness. .................................................................................................................. 78 Table 26: Studies Assessing Drowsiness, Somnolence, Fatigue, or Sedation. ...................................................... 81 Table 27: Studies Assessing Diarrhea. ................................................................................................................... 83

List of Figures Figure 1: WHO-Pain Ladder.(16) ............................................................................................................................. 9 Figure 2: Analytical Framework of the Comparative Efficacy, Effectiveness, and Risk for Harms of Extended-Release Opioids in Patients with Cancer-Related Pain. ........................................................................................ 18 Figure 3: PRISMA Flow Diagram of the Study Selection Process. ......................................................................... 27

List of Appendix-Tables Appendix-Table 1: Pharmaceutical Companies that were Contacted. ............................................................... 101 Appendix-Table 2: High Risk of Bias Studies and Reasons for the Poor Quality Rating. ..................................... 106 Appendix-Table 3: KQ1: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Hydromorphone ER, sorted by Outcomes for KQ1. .............................................................................................................................. 107 Appendix-Table 4: KQ1: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Oral Oxycodone ER, sorted by Outcomes for KQ1. .............................................................................................................................. 108

Appendix-Table 5: KQ1: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Oxycodone plus Naloxone ER, sorted by Outcomes for KQ1. ........................................................................................................................ 109 Appendix-Table 6: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Hydromorphone ER, sorted by Outcomes for KQ2. .............................................................................................................................. 110 Appendix-Table 7: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Oxycodone ER, sorted by Outcomes for KQ2. .............................................................................................................................................. 111 Appendix-Table 8: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Transdermal Fentanyl ER, sorted by Outcomes For KQ2. ............................................................................................................................. 112 Appendix-Table 9: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Oral Oxycodone ER sorted by Outcomes for KQ2. .............................................................................................................................. 113 Appendix-Table 10: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Transdermal Fentanyl ER, sorted by Outcomes for KQ2. ........................................................................................................................ 114 Appendix-Table 11: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Transdermal Buprenorphine ER, sorted by Outcomes for KQ2. .............................................................................................. 115 Appendix-Table 12: KQ2: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Oral Oxycodone ER + Naloxone, sorted by Outcomes for KQ2. ............................................................................................................ 116 Appendix-Table 13: KQ2: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Transdermal Fentanyl ER, sorted by Outcomes for KQ2. .............................................................................................................................. 117 Appendix-Table 14: KQ2: GRADE Ratings for the Comparison Transdermal Fentanyl ER vs. Transdermal Buprenorphine ER, sorted by Outcomes For KQ2. .............................................................................................. 118 Appendix-Table 15: Commonly Used Outcome Measures and Instruments. ..................................................... 119

Opioid Therapy for Cancer-Related Pain

1

1 Executive Summary

The PROSPERO (International Prospective Register of Systematic Reviews:

http://www.crd.york.ac.uk/prospero) registration number of this review is:

CRD42012002153

1.1 Background

Pain is one of the consequences cancer patients fear the most about their disease. Experts

estimate that up to 50% of patients afflicted with malignant tumors will experience pain

during the course of their disease. A recent pan-European survey of cancer-related pain

found that 56% of patients suffered moderate-to-severe pain at least monthly. Pain can

negatively affect a patient’s social life and functional psychology (cognitive, affective, and

behavioral). Inadequate pain control can not only affect a patient’s mood but can also trigger

feelings of anxiety and fear which can then lead to depression and a sense of hopelessness.

Whereas inadequate pain control can have a profound negative impact on quality of life,

some studies suggest that adequate pain control can result in improved survival rates.

Treatment of cancer-related pain is multidisciplinary and includes pharmacological therapy,

anti-tumor treatment (e.g., radiation, surgery and chemotherapy), supportive, non-

pharmacological techniques (including psychological support or behavioral therapy), and

invasive procedures (e.g., nerve blockades, neurolytic procedures, intra-thecal drug

therapy).

Recent guidelines for the pharmacological treatment of cancer pain still refer to the WHO’s

(World Health Organization’s) pain ladder, first published in 1986. The European Medicines

Agency (EMA) and U.S. Food and Drug Administration (FDA) have approved a wide variety of

opioids for relieving acute and chronic pain. In addition, several analgesic options are

available as long-acting medications which offer the promise of prolonged analgesia. Long-

acting opioids, also called sustained-release (SR), controlled-release (CR), modified-release

(MR) or extended-release (ER, XR or XL), are available in both oral and transdermal

http://www.crd.york.ac.uk/prospero)%20of%20this%20review%20i%20ID=CRD42012002153



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formulations. They are administered at regularly scheduled times, for example every 12

hours.

The objective of this review was to compare the benefits and harms of oral or transdermal

extended-release opioids used for treatment of adults with moderate to severe cancer-

related pain. Specifically, we addressed the following research questions (KQs):

Key Question 1: How do extended-release opioids compare in their analgesic efficacy and

effectiveness in treating adult patients with cancer-related pain?

Key Question 2: How do extended-release opioids compare in their risk for harms in treating

adult patients with cancer-related pain?

Key Question 3: How do efficacy, effectiveness, or risk for harms of treatment with

extended-release opioids for cancer-related pain differ for the following subpopulations:

Patients with moderate vs. severe cancer pain?

Patients with breakthrough pain?

Patients with a neuropathic cancer pain component?

Different sex, or different age, ethnic or socioeconomic groups?

Patients taking other commonly prescribed co-analgesics (e.g., non-steroidal

anti-inflammatory drugs, antiepileptic drugs, antidepressants)?

1.2 Methods

During the course of topic development and refinement, we worked with the commissioner

of the report to develop a draft and final protocol for the systematic review process. We

generated an analytic framework, preliminary KQs, and preliminary inclusion/exclusion

criteria in the form of PICOTS (patient populations, interventions, comparators, outcomes,

timing, settings).

To identify articles relevant to each KQ, we searched PubMed, the Cochrane Library,

EMBASE, International Pharmaceutical Abstracts, CINAHL, BIOSIS, and Web of Science. We


3

used either Medical Subject Headings (MeSH) or major headings as search terms when

available and key words when appropriate. We limited the electronic searches to human and

adult populations. Sources were searched from 1980 to July 2012. We manually searched

reference lists of pertinent reviews, included trials, and background articles on this topic to

look for any relevant citations that our searches might have missed. We also explored

various sources for unpublished studies and contacted pharmaceutical companies

requesting any unpublished studies or data relevant for this review.

We developed eligibility (inclusion and exclusion) criteria with respect to patient

populations, interventions, comparators, outcomes, timing, settings, study designs, and

durations for each KQ. We included only studies that were published in English or German

language. For cross-over randomized-controlled studies (RCTs), we used data of the first

study period before the cross-over.

Two trained members of the research team independently reviewed all titles, abstracts, and

full-text articles for eligibility against our inclusion/exclusion criteria. If the reviewers

disagreed, they resolved conflicts by discussion and consensus or by consulting a third

member of the review team. To assess the risk of bias of RCTs for major outcomes of

interest, we used the Cochrane risk of bias tool. For observational studies we employed

predefined criteria based on established guidance.

For studies that met our inclusion criteria and were of low or unclear risk of bias, we

extracted important information into a structured data abstraction form. All data

abstractions were reviewed for completeness and accuracy by a second member of the

team. We recorded intention-to-treat (ITT) results if available.

Because quantitative synthesis was not appropriate (e.g., because of clinical heterogeneity,

insufficient number of similar studies, or variation in reported outcomes), we synthesized

the results qualitatively.

We graded the strength of the available evidence in a four-part hierarchy based on an

approach devised by the GRADE (Grading of Recommendations Assessment, Development

and Evaluation) working group. We used four grades: high, moderate, low, and very low.


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Gradings reflect the strength of the body of evidence to answer KQs with respect to the

comparative efficacy, effectiveness, and risk of harms of extended-release opioids.

1.3 Results

We identified 5,135 citations from searches and reviews of reference lists and screened

3,390 records, after removal of duplicates. Out of those, we retrieved 211 articles for full-

text review for this report. Overall, nine studies met eligibility criteria for this systematic

review. Of the included studies, three were double-blind RCTs, two were non-blinded RCTs,

two were prospective cohort studies, and two were retrospective cohort studies.

Six out of the nine included studies that met eligibility criteria were rated as high risk of bias.

The main reasons for rating RCTs as high risk of bias were high attrition and lack of blinding.

We briefly discuss high risk of bias studies in the report because for many comparisons or

outcomes of interest no studies of better methodological quality were available.

The 12 included long-acting opioids allow for 66 possible drug-to-drug comparisons within

this drug class. For comparative efficacy, however, we found evidence on only three

comparisons; for comparative risk of harm on only nine comparisons. Consequently, we can

neither confirm nor rule out differences in the comparative efficacy and risk of harms for the

majority of comparisons. The available evidence often had serious methodological

shortcomings. Consequently, most of our conclusions have a very high degree of

uncertainty:

The comparative efficacy for improvement of pain intensity, quality of life, functional

capacity, and cognitive functioning was similar among compared drugs.

Discontinuation rates because of lack of evidence were also similar. The strength of

evidence supporting similar efficacy among compared drugs is very low.

We could not find eligible evidence on the comparative efficacy of transdermal

buprenorphine ER, oral dihydrocodeine ER, transdermal fentanyl ER, oral morphine

plus naltrexone ER, oral nalbuphine ER, oxymorphone ER, oral tapentadol

hydrochloride ER, and oral tramadol ER.


5

With few exceptions, the comparative risk of harms was also similar among reviewed

drugs. Discontinuation rates because of adverse events were similar. The strength of

evidence supporting a similar risk of harms with respect to serious adverse events,

constipation, nausea and vomiting, dizziness, and somnolence among compared

drugs is low or very low.

Oral oxycodone ER had higher risks of some adverse events than comparator drugs,

the strength of evidence, however, is low or very low:

o a higher risk of drowsiness than oral hydromorphone ER;

o a higher risk of constipation than oral oxycodone plus naloxone ER;

o a higher risk of nausea than oral morphine ER and transdermal fentanyl ER;

o and a higher risk of somnolence than transdermal fentanyl ER.

We did not find any studies that addressed the comparative efficacy and risk of harms of

extended-release opioids in subgroups with respect to sex, ethnicity, age, patients with

moderate vs. severe cancer pain, breakthrough pain, or pain with a neuropathic component.

Furthermore, no evidence on patients taking other commonly prescribed co-analgesics (e.g.,

non-steroidal anti-inflammatory drugs, antiepileptic drugs, antidepressants) was available.

1.4 Discussion

This systematic review assesses the comparative efficacy and risk of harms of extended-

release opioids for the treatment of moderate to severe cancer-related pain. Overall, for

most interventions and outcomes of interest, evidence was either lacking or insufficient to

draw conclusions. Furthermore, in the evidence available, the eligible studies often had

serious serious methodological shortcomings. Consequently, most of the conclusions have a

very high degree of uncertainty.

The available evidence indicates no substantial differences in efficacy and risk of harms

amongst extended-release opioids. Our confidence in these estimates, however, is very low.

We anticipate that future studies will change these estimates. Given the lack of reliable

evidence regarding the comparative benefits and harms of extended-release opioids,

clinicians should weigh clinical experience, patient preferences, and treatment costs when

choosing the optimal treatment for an individual cancer patient.


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2 Introduction

2.1 Background

2.1.1 Cancer Pain

Pain is one of the consequences cancer patients fear the most about their disease. Experts

estimate that up to 50% of patients afflicted with malignant tumors will experience pain

during the course of their disease(1), although reported prevalence data set the range more

widely at 14 to 100%(2). In a quarter of all cancer patients, pain is the presenting symptom

at the time a tumor is diagnosed.(3) The incidence of pain, however, increases with the

progression of the underlying disease. Eventually two-thirds of patients with advanced,

metastatic cancer will suffer pain. In some types of cancer such as pancreatic cancer and

cancer of the head or neck, pain is especially prevalent.(4) Bone metastases (e.g., in lung,

prostatic or breast cancer) are usually also associated with intense pain conditions. A recent

pan-European survey of cancer-related pain found that 56% of patients suffered moderate-

to-severe pain at least monthly.(1) The International Association for the Study of Pain

defines pain as “an unpleasant sensory and emotional experience associated with actual or

potential tissue damage, or described in terms of such damage”.(5)

Pain can negatively affect a patient’s social life and functional psychology (cognitive,

affective and behavioral). When movement provokes pain, a patient’s daily activities and

mobility will be restricted. Inadequate pain control can not only affect a patient’s moods but

can also trigger feelings of anxiety and fear which can then lead to depression and a sense of

hopelessness.(6) Whereas inadequate pain control can have a profound negative impact on

quality of life, some studies suggest that adequate pain control can result in improved

survival rates.(1, 7)

Multiple causes exist for cancer-related pain. These can be roughly grouped into three

categories. First, the tumor or its metastases may directly cause pain. Second, in about 20%

of patients, cancer treatment results in painful sequelae such as painful peripheral

neuropathy after chemotherapy, persisting pelvic pain after radiation therapy or post-


7

thoracotomy pain after surgery.(8) Third, older patients in particular may suffer from pain

unrelated to the tumor that stems from preexisting chronic pain (e.g., chronic back pain

osteoarthritis or painful diabetic peripheral neuropathy). Sometimes patients report pain of

a fourth category - pain related to cancer such as muscle spasms, constipation, or

bedsores.(9)

Pain can be classified according to the underlying pathophysiology in nociceptive or

neuropathic pain. Direct tissue injury resulting in activation of nociceptors causes

nociceptive pain. Nociceptive pain can be further classified as either somatic or visceral.

Examples of conditions that cause nociceptive pain in cancer patients are bone metastases,

tissue inflammation and edema for somatic pain, or tumor invasion and distension of

internal organs as in peritoneal carcinosis or hepatic metastases for visceral pain.

Neuropathic pain on the other hand, is caused by infiltration or compression of peripheral or

central (e.g., spinal cord metastases) neuronal structures. While the distinction between

somatic and neuropathic pain has therapeutic implications – neuropathic pain usually does

not respond well to classical analgesics – the specification is also somewhat theoretical,

since patients suffering from cancer pain typically suffer from mixed types of pain in multiple

locations.(10) Assessment of pain quality can provide some clues as to the type of pain.

Somatic pain is usually localized and described as aching or throbbing, visceral pain is rather

diffuse, also described as cramping, whereas descriptions for neuropathic pain might include

shooting, burning or electrical sensations.

Caregivers and patients can also categorize pain according to its severity. Assessment of pain

intensity is usually based on self-reporting tools, using visual analogue scales (VAS) or

numerical rating scales (NRS), which are considered equally efficient.(11) On numerical

scales, scores from 0-4 generally indicate mild, 5-6 moderate, and 7-10 severe pain(12),

although some authors see the boundary between moderate and severe pain at >7.(13)

Verbal rating scales with four to seven adjectives describing pain intensity are used as well.

When assessments of pain focus solely on intensity, other dimensions of pain, particularly

pain induced impairment, are left unaccounted for. Multidimensional questionnaires are

more appropriate for assessing pain induced impairments.(14, 15)


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Finally, pain assessments need to consider the time course of pain, especially if the pain is

stable or intermittent.

2.1.2 Treatment Strategies (Opioids)

Treatment of cancer-related pain is multidisciplinary and includes pharmacological therapy,

anti-tumor treatment (e.g., radiation, surgery and chemotherapy), supportive, non-

pharmacological techniques (including psychological support or behavioral therapy) and

invasive procedures (e.g., nerve blockades, neurolytic procedures, intra-thecal drug

therapy).

Recent guidelines for the pharmacological treatment of cancer pain(16) still refer to the

WHO’s (World Health Organization’s) pain ladder, first published in 1986 (see Figure 1).(17)

The WHO-ladder recommends a graded approach based on pain severity. For mild pain (NRS

1-4) non-opioid analgesics (non-steroidal anti-inflammatory drugs [NSAIDS] or

paracetamol/acetaminophen) might be sufficient in WHO-step I. When the pain is moderate

(up to NRS 5-7) WHO-step II suggests the addition of weak opioids (codeine, dihydrocodeine

or tramadol). Although not included in the original WHO pain ladder, some authors also

include strong opioids in low doses for WHO-step II.(16) For severe pain (NRS 8-10) strong

opioids replace codeine or tramadol (Figure 1). The ladder lists morphine as a “standard”

strong opioid although other drugs such as hydromorphone, transdermal fentanyl,

transdermal buprenorphine, or oxycodone are mentioned as well. The combination of

opioids with non-opioid analgesics is intended to reduce the side effects of opioids.(18)

Clinicians usually prefer the oral administration of pharmacological treatments.(17)

Transdermal opioid delivery systems (e.g., transdermal fentanyl or transdermal

buprenorphine), which take longer to reach a steady-state, may be more appropriate in

certain patients like those who have difficulty swallowing or adhering to treatment

regimens.(16) Clinicians reserve more invasive routes of opioid administration (e.g.,

subcutaneous, intravenous, or the spinal route) for patients in whom adequate analgesia

cannot be otherwise achieved. Drugs should be administered at fixed time intervals – “by

the clock”, using “rescue-medication” i.e., immediate-release preparations for breakthrough

pain. Adjuvants and co-analgesics (e.g., antidepressants or anti-convulsive drugs) might be

used at every step of the WHO ladder as clinically appropriate.(17)


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WHO III Strong opioid (morphine hydromorphone, transdermal fentanyl,

transdermal buprenorphine, oxycodone, …)

Non-opioid analgesic

Adjuvant analgesic

WHO II Weak opioid (codeine, dihydrocodeine, tramadol)

Non-opioid analgesic

Adjuvant analgesic

WHO I Non-opioid analgesic (non-steroidal anti-inflammatory drug NSAIDS or paracetamol/acetaminophen)

Adjuvant analgesic

Adjuvant analgesics (antidepressant, anticonvulsive drugs, …)

supportive measures

Figure 1: WHO-Pain Ladder.(16)

Opioids, while effective for treating cancer pain(19), also come with a multitude of adverse

effects.(20) Common side effects involve the central nervous system and include drowsiness,

sedation, or cognitive impairment. Patients, however, usually develop tolerance to these

adverse events. The major reasons for discontinuation of opioid therapy are typical

gastrointestinal side effects such as nausea and constipation.(21) Less common , but still

clinically relevant side effects, are the symptoms ascribed to opioid induced central nervous

system hyperexcitability which include confusion, hallucinations and myoclonic jerks.(16)

Rarely, opioid-induced hyperalgesia necessitates either a dose reduction or opioid rotation.

Moreover, opioids can cause urinary retention, pruritus, and sleep disturbances. They can

also contribute to depression. Opioids compromise the immune system and some believe

they may aid tumor growth.(22) Last but not least, opioids have hormonal effects on

testosterone and estrogen that can result in sexual dysfunction.

Opioids are extensively prescribed; in 2011, an estimated 22.9 million prescriptions for

extended-release opioids were dispensed in the U.S.(23) Opioids also have a risk for misuse,

and abuse which can lead to overdoses, addiction, and even deaths.(23)

Pain

persistin

g o

r increa

sing


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2.1.3 Pharmacology of Analgesic Opioids

Opioids produce their analgesic effects by binding to three major receptor families which are

called µ (mu), (kappa), and (delta) receptors. Although these receptors exist throughout

the body’s tissues, they are mainly located in the central nervous system.(24)

Classification of opioid analgesics as either pure agonists or agonist-antagonists is based on

their interaction with opioid receptors. The agonist-antagonists are divided into two

subtypes: partial agonists and mixed agonist-antagonists. Pure opioid agonists (morphine,

codeine, oxycodone, hydromorphone, fentanyl) bind to opioid receptors avidly and have no

ceiling in their analgesic effects. Opioids in the mixed agonist-antagonist subclass

(nalorphine, pentazocine) generally are not used for chronic pain because they have a ceiling

effect for antinociception and usage may result in the development of withdrawal

symptoms. Partial opioid agonists like buprenorphine have high affinity binding to opioid

receptors but low efficacy and produce a sub-maximal effect compared to pure agonists.(25-

27)

Tramadol can be considered an atypical opioid analgesic that acts through both an opioid

(mu agonist) and a nonopioid (serotonergic and noradrenergic) mechanism.(25-27)

Tapentadol is another narcotic pain reliever that has been marketed since 2008. It is a

centrally acting oral analgesic with two mechanisms of action within the same molecule: an

agonist activity at the mu-opioid receptor and a noradrenaline reuptake inhibition. The latter

characteristic makes it potentially more effective in treating neuropathic pain.(28)

Patient responses to opioid therapy vary remarkably, inter-individually from opioid to opioid

and also at different stages of treatment. Inadequate pain relief or intolerable side effects

are the main reasons for changes in treatment. Clinicians might recommend administration

of the same opioid through an alternative route or change to another agent.(29, 30)

The EMA and the FDA have approved a wide variety of opioids for relieving acute and

chronic pain. In addition, several analgesic options are available as long-acting medications

which offer the promise of prolonged analgesia. Long-acting opioids, also called sustained-

release (SR), controlled-release (CR), modified-release (MR), or extended-release (ER, XR, or


11

XL), are available in both oral and transdermal formulations. They are administered at

regularly scheduled times, for example every 12 hours (Table 1).

Table 1: Extended-Release Opioid Analgesic Products.

Analgesic Usual Interval Label Indication

Transdermal Buprenorphine ER

4 days (Transtec®), 7 days (Butrans®, Norspan®)

Management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Dihydrocodeine ER 12 h Relief of severe pain in cancer and other chronic conditions

Transdermal Fentanyl ER

72 h (3 days) Management of persistent, moderate to severe chronic pain in opioid-tolerant patients 2 years of age and older that:

requires continuous, around-the-clock opioid administration for an extended period of time, and

cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids

Hydromorphone ER 12h or 24h Management of moderate-to-severe pain in opioid-tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time

Morphine ER 12 h Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Morphine ER + Naltrexone

12h or 24h Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time*

Oxycodone ER 12 h Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Oxycodone ER + Naloxone

12h Relief of moderate to severe pain in adults who require continuous, around-the-clock opioid analgesia for several days or more. The naloxone component is indicated for the relief of opioid-induced constipation (OIC)

Oxymorphone ER 12 h Relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time

Tapentadol hydrochloride ER

12 h Management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Tramadol ER 24 h Management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time

Abbreviations: ER, extended-release; h, hour; OIC, opioid-induced constipation; SR, sustained release.

*No longer being marketed, but it is still approved.

Compared to classic short-acting formulas, extended-release opioid delivery systems reduce

the frequency a patient is required to administer the medication. Table 2 lists extended-

release opioids, commercially available in Austria, Switzerland, Germany, the UK (United

Kingdom) and the U.S. (United States). Transdermal Buprenorphine, transdermal fentanyl,


12

hydromorphone, morphine, oxycodone, oxymorphone, and tramadol are also available as

generic products.

Slow release into the body via controlled-release preparations of a short-acting agent

account for the prolonged analgesic effects of these agents. Various methods exist to extend

the release of oral opioids. These include usage of a simple matrix system(31) or new

technologies like osmotic-controlled release oral delivery system (OROS)(32) or spheroidal

oral drug absorption system (SODAS)(33) or chemical modification of the drug such as

glucoronating morphin.(34) Administration of a physical matrix entrapment of the drug

compound such as polymeric matrix system technology can control the release of

transdermal delivery opioids.(35)

Table 2: Extended-Release Opioids Approved for Treatment of Moderate to Severe Pain in Austria1, Switzerland

2,

Germany3, UK

4, and US

5.

Generic Names Trade Names Route of Administration

Formulation

Buprenorphine ER

AT Transtec®

Transdermal system

TDP 35, 52.5, 70 μg/h

CH

Transtec®

Transdermal system

TDP 35, 52.5, 70 μg/h

DE

Acimaphin®, BUP-4®, Transtec®, Transtec PRO®, Trapamaphin®

Transdermal system

TDP 35, 52.5, 70 μg/h

Norspan® Transdermal system TDP 5, 10, 20 μg/h

UK

BuTrans®

Transdermal system

TDP 5, 10, 20 μg/h

Transtec® Transdermal system TDP 35, 52.5, 70 μg/h

US

Butrans®

Transdermal system

TDP 5, 10, 20 μg/h

Dihydrocodeine ER

AT Codidol® retard, Dehace® retard

Oral

Tab 60, 90, 120 mg

CH Codicontin®

Oral

Tab 60, 90, 120 mg

DE DHC Continus®, DHC Mundipharma®

Oral

Tab 60, 90, 120 mg

UK DHC Continus®

Oral

Tab 60, 90, 120 mg

Fentanyl ER AT Fentaplast®

Transdermal system

TDP 25, 50, 75, 100 μg/h


13


Formulation

Fentarichtex® Transdermal system TDP 25, 37.5, 50, 75, 100 μg/h Durogesic®, Lafene®,

Fentoron®, Matrifen® Transdermal system TDP 12, 25, 50, 75, 100 μg/h

CH Durogesic Matrix®, Matrifen®

Transdermal system

TDP 12, 25, 50, 75, 100 μg/h

DE Fentavera®, Fentalupo Matrix®, Durogesic SMAT®, Fentaderm®, Fentadolon®, Fenylat®, Fentaquick Matrix®, Fentareu Matrix®, Matrifen®

Transdermal system

TDP 12, 25, 50, 75, 100 μg/h

FentaMat Sandoz® Transdermal system TDP 12, 25, 37.5, 50, 75, 100 μg/h Fenta Regiomedica

Matrix®, Durogesic®, Fentil®, Fentrix®, Lavifent Fentapatch Matrix®, Fentatrans®

Transdermal system TDP 25, 50, 75, 100 μg/h

UK Fencino®, Durogesic Dtrans®, Matrifen®, Mezolar Matrix®, Tilofyl®, Osmanil®

Transdermal system

TDP 12, 25, 50, 75, 100 μg/h

Victanyl® Transdermal system TDP 25, 50, 75, 100 μg/h

US Duragesic®

Transdermal system

TDP 12, 25, 50, 75, 100 μg/h

Hydromorphone ER

AT Jurnista®

Oral

Tab 4, 8, 16, 32, 64 mg

Hydal retard® Oral Cap 2, 4, 8, 16, 24 mg Mydrophostad® Oral Tab 4, 8, 16, 24 mg

CH Jurnista®

Oral

Tab 4, 8, 16, 32 mg

Palladon® Retard Oral Cap 4, 8, 16, 24 mg

DE Jurnista®

Oral

Tab 4, 8, 16, 32, 64 mg

Palladon Uno® Oral Cap 12, 16, 24, 32 mg Palladon® retard Oral Cap 4, 8, 16, 24 mg

UK Palladone® SR

Oral

Cap 2, 4, 8, 16, 24 mg

US Exalgo®

Oral

Tab 8, 12, 16 mg

Palladone®* Oral Cap 12, 16, 24, 32 mg

Morphine ER AT Compensan® retard

Oral

Tab 100, 200, 300 mg


14


Formulation

Kapanol CSR® Oral Cap 50, 100 mg M - dolor® retard Oral Cap 10, 30, 60, 100, 200 mg Mundidol® retard,

Vendal® retard Oral Tab 10, 30, 60, 100, 200 mg

Mundidol Uno® retard Oral Cap 30, 60, 120, 200 mg Relimal® Oral Tab 200 mg Substitol® retard Oral Cap 120, 200 mg

CH Kapanol®

Oral

Cap 20, 50, 100 mg

M-retard Helvepharm® Oral Tab 10, 30, 60, 100, 200 mg MST Continus® Oral Susp 20, 30, 60, 100, 200 mg Sevre-Long® Oral Cap 30, 60, 120, 200 mg

DE Capros®

Oral

Cap 10, 20, 30, 60, 120, 200 mg

M-beta®, Morph Sandoz®, Morph® retard, Morphanton®, Morpholar®

Oral Tab 10, 30, 60, 100 mg

M-long® Oral Cap 10, 30, 60, 100 mg MST Mundipharma®,

MSTW Krugmann® Oral Tab 10, 30, 60, 100, 200 mg

Kapanol®, Morsan® Oral Cap 20, 50, 100 mg MST Continus® Oral Cap 30, 60, 100, 200 mg MST Retard-Granulat® Oral Gran 30, 60, 100, 200 mg M-Stada® Oral Tab 30, 60, 100, 200 mg Zomorph® Oral Cap 20, 40, 60, 120, 200 mg

UK Morphgesic® SR

Oral

Tab 10, 30, 60, 100 mg

MST Continus® Oral Tab 5, 10, 15, 30, 60, 100, 200 mg MST Continus® Oral Susp 20, 30, 60, 100, 200 mg MXL® Oral Cap 30, 60, 90, 120, 150, 200 mg Filnarine® SR, Zomorph® Oral Tab 10, 30, 60, 100, 200 mg

US Avinza®

Oral

Cap 3, 45, 60, 75, 90, 120 mg

Kadian® Oral Cap 10, 20, 30, 50, 60, 80, 100, 200 mg MS Contin® Oral Tab 15, 30, 60, 100, 200 mg Oramorph SR® Oral Tab 15, 30, 60, 100 mg


US Embeda®*

Oral

Cap 20/0.8, 30/1.2, 50/2, 60/2.4, 80/3.2, 100/4 mg

Oxycodone ER AT Carenox®

Oral

Tab 5, 10, 20 mg

Merlodon® Oral Tab 20, 30, 40, 50, 60, 80 mg Maridolor® Oral Tab 20, 40, 80 mg OxyGerolan®,

OxyContin® retard Oral Tab 5, 10, 20, 40, 80 mg

CH OxyContin® Retard

Oral

Tab 5, 10, 20, 40, 80 mg

DE


15


Formulation

Kancodal HEXAL® Oral Tab 10, 20 mg OxyContin®, Oxygesic® Oral Tab 5, 10, 20, 40, 80 mg

UK OxyContin®

Oral

Tab 5, 10, 15, 20, 30, 40, 60, 80, 120 mg

US OxyContin®

Oral

Tab 10, 15, 20, 30, 40, 60, 80, 160 mg


AT Targin®, Retardtabletten

Oral

Tab 5/2,5, 10/5, 20/10, 40/20 mg

CH Targin®, Retardtabletten

Oral

Tab 5/2,5, 10/5, 20/10, 40/20 mg

DE Oxynal®, Retardtabletten

Oral

Tab 10/5, 20/10 mg

Targin®, Retardtabletten Oral Tab 5/2,5, 10/5, 20/10, 40/20 mg

UK Targinact®

Oral

Tab 5/2.5, 10/5, 20/10, 40/20 mg

Oxymorphone ER US Opana® ER

Oral

Tab 5, 7.5, 10, 15, 20, 30, 40 mg


DE Palexia® retard

Oral

Tab

Yantil® retard Oral Tab

UK Palexia® SR

Oral

Tab 50, 100, 150, 200, 250 mg

US Nucynta® ER

Oral

Tab 50, 100, 150, 200, 250 mg

Tramadol ER AT Adamon® SR

Oral

Cap 50, 100, 150, 200 mg

Adamon® long retard Oral Tab 150, 200, 300, 400 mg Contramal® retard,

Nobligan® retard Oral Tab 50 mg

Cromatodol® Oral Cap 100, 200 mg Lanalget® retard,

Tradolan® retard, Tramal® retard, Tramabene®, Tramadolor® retard, Tramundal® retard

Oral Tab 100, 150, 200 mg

Noax uno® Oral Tab 100, 200, 300 mg Tramadolor Uno® retard Oral Tab 200 mg

CH Tramal® retard, Tramundin®

Oral

Tab 100, 150, 200 mg

Tramactil Uno® Oral Tab 100, 200, 300 mg Tradonal one® Oral Tab 150, 200, 300, 400 mg


16


Formulation

DE CG 315/1 long, Tramadura®, Tramdol® Retard

Oral

Tab 100 mg

Amadol® Retard, Nobligan® retard, Tramal® retard

Oral Tab 50, 100, 150, 200 mg

Amadol®, Tramabeta long®, Tramabeta® retard, Tramadolor ID®, Tramagit®, Tramal long®, Tramamed®, Tramil® RT, Tramol® RT, Tramundin® retard

Oral Tab 100, 150, 200 mg

Tramalgin® RT Oral Tab 150, 200 mg Hexamadol® Retard,

Hexatram® Retard, Tramasan® Retard

Oral Tab 200 mg

T-Long®, Tramabene Uno®

Oral Cap 100, 150, 200 mg

Tramadolor® einmal täglich

Oral Tab 100, 200, 300 mg

Travex One® Oral Tab 150, 200, 300, 400 mg

Tramadolor long®, Tramadura®, Travex® retard

Oral Cap 50, 100, 150, 200 mg

UK Larapam®, Mabron®, Marol®, Zeridame SR®, Zydol SR®

Oral

Tab 100, 150, 200 mg

Tradorec XL® Oral Tab 100, 200, 300 mg

Zamadol® 24hr, Zydol XL®

Oral Tab 150, 200, 300, 400 mg

Maxitram®SR Oral Tab 50, 100, 150, 200 mg Tramquel® SR,

Zamadol® SR Oral Cap 50, 100, 150, 200 mg

US Conzip®

Oral

Cap 50, 100, 150, 200 mg

Ryzolt®, Ultram® ER Oral Tab 100, 200, 300 mg

* No longer being marketed

Abbreviations: AT, Austria; Cap, capsule; CH, Switzerland; DE, Germany; ER, extended-release; Gran, Granule; h, hour; mg, milligram; RT, retard; SR, sustained-release; Susp, suspension; Tab, tablet; TDP, trans-dermal patch; UK, United Kingdom; US, United States; XL, extended length; μg, microgram. 1Austria: Austria Codex. Retrieved January 28, 2012 from http://www.univadis.at/ 2Switzerland: Medicinal product information. Swiss Agency for Therapeutic Products. Retrieved January 28, 2012 from http://swissmedinfo.oddb.org/ 3Germany: AMIS Drug Information System. German Institute of Medical Documentation and Information. Retrieved January 28, 2012 from http://www.dimdi.de/static/en/amg/amis/index.htm 4UK: British National Formulary. 61st edition. 2011. British Medical Association and Royal Pharmaceutical Society of Great Britain. UK: The electronic Medicines Compendium (eMC). Retrieved January 28, 2012 from http://www.medicines.org.uk/ 5US: Drugs@FDA: FDA Approved Drug Products. U.S. Food and Drug Administration. Retrieved January 28, 2012 from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

http://www.univadis.at/

http://swissmedinfo.oddb.org/

http://www.dimdi.de/static/en/amg/amis/index.htm

http://www.medicines.org.uk/EMC/Default_beta.aspx

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm


17

2.2 Scope and Key Questions

This review compares the efficacy, efficacy and harms of oral or transdermal extended-

release opioids used for treatment of adults with moderate to severe cancer-related pain.

We also address the clinical importance of subgroup status that may affect efficacy, efficacy,

and harms; these include sex, age, ethnic or socioeconomic groups, intensity and quality of

pain, and patients taking various co-analgesics. We approach each key question by

considering the relevant populations, interventions, comparators, outcomes, timing, and

settings (PICOTS). In this review, we address the following Key Questions (KQs):

Key Question 1: How do extended-release opioids compare in their analgesic efficacy and

effectiveness in treating adult patients with cancer-related pain?

Key Question 2: How do extended-release opioids compare in their risk for harms in treating

adult patients with cancer-related pain?

Key Question 3: How do efficacy, effectiveness, or risk for harms of treatment with

extended-release opioids for cancer-related pain differ for the following subpopulations:

Patients with moderate vs. severe cancer pain?

Patients with breakthrough pain?

Patients with a neuropathic cancer pain component?

Different sex, or different age, ethnic or socioeconomic groups?

Patients taking other commonly prescribed co-analgesics (e.g., non-steroidal

anti-inflammatory drugs, antiepileptic drugs, antidepressants)?

Figure 2 depicts the analytic framework for the comparative efficacy, effectiveness and risk

of harms for extended-release opioids in adult patients with moderate to severe cancer pain.

KQs are displayed within the context of the PICOTS described in more detail in Methods.

Beginning with a population of adults with cancer-related pain, the figure illustrates the

comparative effects of extended-release opioids on health outcomes, including pain


18

intensity, quality of life, functional capacity, patient perceived effectiveness and cognitive

performance (KQ1). KQ2 addresses the comparative risks of opioid-related harms from these

interventions. Finally, subgroups within the overall population will be identified based on

sex, age, ethnic or socioeconomic groups, intensity and quality of pain, and patients taking

various co-analgesics (KQ3).

Figure 2: Analytical Framework of the Comparative Efficacy, Effectiveness, and Risk for Harms of Extended-Release Opioids in Patients with Cancer-Related Pain.

Adverse effects of intervention

(KQ2)

Serious adverse events

Constipation

Nausea and vomiting

and other adverse events

Discontinuation of

treatment:

Due to lack of

efficacy (KQ1)

Due to adverse

events (KQ2)

Differences in (KQ1):

Pain relief

Quality of life

Patient perceived

effectiveness

and other health-related

outcomes

Extended-release opioids

Adult patients with cancer-

related pain

Subgroups: (KQ3)

1 Sex

2 Age

3 Ethnic groups

4 Socioeconomic groups

5 Intensity and quality of pain

6 Patients taking co-analgesics


19

3 Methods

The PROSPERO (International Prospective Register of Systematic Reviews:

http://www.crd.york.ac.uk/prospero) registration number of this review is:

CRD42012002153

The main sections in this chapter reflect the elements of the protocol established for the

review. All methods and analyses were determined a priori.

3.1 Topic Refinement and Review Protocol

During the course of topic development and refinement, we worked with the commissioner

of the report to develop a draft and final protocol for the systematic review process. We

generated an analytic framework, preliminary KQs, and preliminary inclusion/exclusion

criteria in the form of PICOTS. The processes were guided by the information provided by

the funder of the review, a scan of the literature, and methods and content experts.

3.2 Search Strategy

To identify articles relevant to each KQ, we searched PubMed, the Cochrane Library,

EMBASE, International Pharmaceutical Abstracts, CINAHL, BIOSIS and Web of Science. The

full search strategy is presented in Appendix A. We used either Medical Subject Headings

(MeSH) or major headings as search terms when available and key words when appropriate,

focusing on terms to describe the relevant populations and interventions of interest. We

limited the electronic searches to human and adult populations. Sources were searched

from January 1980 to July 2012. We manually searched reference lists of pertinent reviews,

included trials, and background articles on this topic to look for any relevant citations that

our searches might have missed. We imported all citations into an EndNote® X4 electronic

database. Searches were run by an experienced information scientist.

We also searched for unpublished studies (i.e., grey literature) relevant to this review using

OpenGrey (http://www.opengrey.eu/), the GlaxoSmithKline Study Register (http://www.gsk-

clinicalstudyregister.com/), ClinicalTrials.gov (http://clinicaltrials.gov/), Drugs@FDA




20

(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/), the World Health Organization’s

International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/), and the

National Cancer Institute’s Clinical Trial Database (http://www.cancer.gov/clinicaltrials). In

addition, we contacted pharmaceutical companies requesting any unpublished studies or

data relevant for this review (see Appendix B). To include information from the

pharmaceutical industry, we required studies to meet all inclusion criteria and to contain

enough information on research methods to be able to assess risk of bias. Furthermore, we

contacted all authors from studies published only as abstracts to ascertain if these abstracts

were ever published as full papers and could be included in our study. Finally, in cases in

which relevant information was unclear or not reported, we contacted authors in an attempt

to obtain additional or unpublished information.

3.3 Eligibility Criteria

We developed eligibility (inclusion and exclusion) criteria with respect to patient

populations, interventions, comparators, outcomes, timing, settings, study designs, and

durations for each KQ. We included only studies that were published in English or German

language. For cross-over RCTs, we used data of the study period before the cross-over only.

3.3.1 Population

Adult patients with moderate or severe cancer-related pain of any aetiology; aetiology may

be primary or secondary malignancy from solid or haematological tumours. Studies

investigating the efficacy of medications for the treatment of breakthrough pain were

excluded.

3.3.2 Intervention

Oral or transdermal extended-release opioids (WHO level III or WHO level II if approved for

moderate to severe pain in Germany, Austria, Switzerland, the United Kingdom, or the

United States; listed in Table 3)


21

Table 3: Included Drugs and Combination of Drugs.

Generic Name


Dihydrocodeine ER


Hydromorphone ER

Morphine ER


Nalbuphine*

Oxycodone ER


Oxymorphone ER


Tramadol ER

*It is under development and has not approved yet. Abbreviations: ER, extended-release; SR, sustained-release.

3.3.3 Control

Any included drug as listed in Table 3. We initially considered other active controls or

placebo to conduct indirect comparisons. Because of lack of data we could not further

pursue this approach.

3.3.4 Outcomes

Table 4 summarizes included outcomes of interest and eligible study designs.


22

Table 4: Outcomes and Eligibility Criteria.

Outcome Study Eligibility Criteria

Efficacy / effectiveness

Health outcomes: o Pain intensity (patient-reported) o Quality of life (patient-reported) o Functional capacity o Patient perceived effectiveness o Cognitive performance

Discontinuation due to lack of efficacy / effect

Head-to-head double-blind RCTs1 or

systematic reviews +/- meta-analysis comparing 1 opioid to another o Low or unclear risk of bias o ≥ 1 week study duration

Risk for Harms

Overall adverse events

Serious adverse events

Specific adverse events, including: o Nausea and vomiting o Constipation o Dizziness o Drowsiness o Somnolence o Fatigue

Discontinuations due to adverse events

Head-to-head double-blind RCTs or systematic reviews +/- meta-analysis comparing 1 opioid to another o Low or unclear risk of bias o ≥ 1 week study duration

Open label or single-blinded RCTs (head-to-head), controlled observational studies (prospective and retrospective) o Low or unclear risk of bias o ≥ 1 week study duration o n ≥ 100

Abbreviations: n, number of participants; RCT, randomized controlled trial.

3.3.5 Timing

Studies with a duration of at least one week were eligible for this review.

3.3.6 Setting

We considered any setting.

3.4 Study Selection

We developed and pilot-tested literature review forms for abstract and full-text reviews (see

Appendix C). Two trained members of the research team independently reviewed all titles

and abstracts (identified through searches) for eligibility against our inclusion/exclusion

criteria. Studies marked for possible inclusion by either reviewer underwent a full-text

review. For studies that lacked adequate information to determine inclusion or exclusion, we

retrieved the full-text and then made the determination. If the necessary information in full-

1 for cross-over designs, we used only data after the first period before the cross-over.


23

text articles was unclear or missing, we contacted authors of the publications. All results

were tracked in an EndNote® database.

We retrieved the full-texts of all articles included during the title and abstract review phase.

Two trained members of the research team independently reviewed each full-text article for

inclusion or exclusion based on the eligibility criteria described above. If both reviewers

agreed that a study did not meet the eligibility criteria, we excluded it. If the reviewers

disagreed, they resolved conflicts by discussion and consensus or by consulting a third

member of the review team. All results were tracked in an EndNote® database. We recorded

the principal reason that each excluded full-text publication did not satisfy the eligibility

criteria (Appendix H).

3.5 Data Extraction

For studies that met our inclusion criteria and were of low or unclear risk of bias, we

extracted important information into a structured data abstraction form. We designed, pilot-

tested, and used structured data extraction forms to gather pertinent information from each

article; this included characteristics of study populations, settings, interventions,

comparators, study designs, methods, and results. Trained reviewers extracted the relevant

data from each included article into the data extraction forms. All data abstractions were

reviewed for completeness and accuracy by a second member of the team. We recorded

intention-to-treat (ITT) results if available. All data abstraction was performed using

Microsoft Excel® software. We did not extract complete data from studies that we rated as

high risk of bias.

3.6 Risk of Bias Assessment of Individual Studies

To assess the risk of bias (internal validity) of studies for major outcomes of interest, we

used the Cochrane risk of bias tool.(36) For observational studies we employed predefined

criteria as outlined by Deeks et al.(37) We assessed selection bias, confounding,

performance bias, detection bias, and attrition bias; we included questions about adequacy

of randomization, allocation concealment, similarity of groups at baseline, masking, attrition,


24

whether ITT analysis was used, method of handling dropouts, and treatment fidelity. We

rated the studies as low, unclear, or high risk of bias.

In general terms, a study categorized as low risk of bias implies confidence that results

represent the true treatment effects. A study with unclear risk of bias is susceptible to some

risk of bias but probably not enough to invalidate its results. A study assessed as high risk of

bias has significant flaws of various types (e.g., stemming from serious errors in design,

conduct, or analysis) that may invalidate its results.

Two independent reviewers assessed the risk of bias for each study; one of the two

reviewers was always an experienced or senior investigator. Disagreements between the

two reviewers were resolved by discussion and consensus or by consulting a third member

of the team. Appendix D lists studies rated as high risk of bias and reasons for the risk of bias

rating.

In addition to methodological shortcomings, we also assessed the dosing equivalence of

drugs compared within the same study. We used the equianalgesic dose calculator of the

Johns Hopkins University (www.hopweb.org).

3.7 Data Synthesis

Because quantitative synthesis was not appropriate (e.g., because of clinical heterogeneity,

insufficient number of similar studies, or variation in reported outcomes), we synthesized

the results qualitatively.

3.8 Strength of Body of Evidence

We graded the strength of the available evidence in a four-part hierarchy based on an

approach devised by the GRADE (Grading of Recommendations Assessment, Development

and Evaluation) working group.(38) As shown in Table 5 we used four grades: high,

moderate, low, and very low. Gradings reflect the strength of the body of evidence to

answer key questions with respect to the comparative efficacy, effectiveness, and risk of

harms of extended-release opioids.

http://www.hopweb.org/


25

Table 5: Definitions of the Grades of the Overall Quality of Evidence.

High We are very confident that the true effect lies close to that of the estimate of the effect

Moderate We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

Low Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

Very Low We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Source: Adapted from the GRADE working group.(39)

This approach does not incorporate other factors that might be relevant to assess reliably

the comparative efficacy, effectiveness, and harms, such as funding sources. We dually

evaluated the overall strength of evidence for each major outcome based on a qualitative

assessment of strength of evidence for each domain. We reconciled all disagreements in

grades through consensus discussion.

We graded the strength of the body of evidence with respect to six outcomes viewed as

critical for decision-making (see Table 6). We selected these outcomes a priori with input

from the clinical expert and the commissioner of the report. Two reviewers assessed each

domain for each key outcome and determined a grade for the strength of evidence. They

resolved any differences by consensus discussion. For each assessment, one of the two

reviewers was always an experienced or senior investigator. The principal focus in the results

will be on these outcomes but we will also comment on other outcomes of interest.

Table 6: Outcomes Viewed as Critical or Important for Decision-Making.

Outcomes Importance of Outcomes

Efficacy/Effectiveness of Interventions

Pain intensity Critical

Quality of life Critical

Patient perceived effectiveness Critical

Functional capacity Important

Cognitive Performance Important

Harms of Interventions

Serious adverse events Critical

Constipation Critical

Nausea and vomiting Critical

Dizziness Important

Drowsiness Important

Somnolence Important

Fatigue Important


26

4 Results

4.1 Introduction

This chapter is organized as follows: First, we discuss general results of the literature

searches and characteristics of included studies. Next, we present the available evidence by

KQ. Within each KQ we present results on the comparative efficacy, effectiveness, or risk of

harms first by outcome and second by individual drug-to-drug comparisons. In addition, we

present key points and a detailed synthesis in each KQ section. For each outcome deemed to

be critical for decision making, we rated the strength of evidence. Appendix E contains the

GRADE evidence profiles which present the ratings of each domain for each critical outcome.

Manufacturers of opioids use different terms to indicate extended-release formulations such

as sustained-release, controlled-release, prolonged-release, or long-acting. To ease

readability, we use only the term extended-release or the abbreviation ER. Unless otherwise

stated, the route of administration is oral. If not stated otherwise, the described extended

release opioids are administered orally.

Studies reviewed for this report employed a notable array of scales to assess outcomes of

interest. Most were pertinent to pain and specific adverse events, but some are considered

more generic instruments that assess aspects such as health-related quality of life, for

example. Appendix F summarizes commonly used instruments and the meaning of scores.

Appendix G defines commonly used abbreviations in this report.

4.2 Results of Literature Searches

We identified 5,135 citations from searches and reviews of reference lists and screened

3,390 records, after removal of duplicates. Figure 3 documents the disposition of the 211

articles retrieved for full-text review for this report. Overall, we included nine studies, and

excluded 202 articles for various reasons. Articles excluded during full-text review are listed

in Appendix H with reasons for exclusions.


27

Figure 3: PRISMA Flow Diagram of the Study Selection Process.

4.3 Description of Included Studies

Overall, nine studies met eligibility criteria for this systematic review. Of the included

studies, three were double-blind RCTs,(40-42) two were non-blinded RCTs,(43, 44) two were

prospective cohort studies(45, 46) and two were retrospective cohort studies.(47, 48) The

three double-blind RCTs assessed head-to-head comparisons. Six out of the nine included

studies were rated as high risk of bias (Appendix D). The main reasons for rating RCTs as high

risk of bias were high attrition and lack of blinding. We briefly discuss high risk of bias studies

4,556 of records

identified through

database searching

579 of additional records identified through

other sources (checking reference lists, trial

registry, contacting pharma companies)

3,390 records after duplicates removed

3,390 records screened 3,179 records excluded

211 full-text articles

assessed for eligibility

9 studies included in

qualitative synthesis

0 studies included in

quantitative synthesis

(meta-analysis)

202 of full-text articles excluded

20 – Ineligible publication type

36 – Ineligible study design

23 – Ineligible duration

12 – Ineligible population

24 – Ineligible intervention

6 – Ineligible administration

10 – Ineligible comparator

9 – Ineligible outcome

13 – Ineligible research question

8 – Ineligible language

10 – Full-text not available

24 – Published as abstract only

7 – Active-controlled study

Iden

tifi

cati

on

S

cre

en

ing

E

lig

ibilit

y

Inclu

de

d


28

in the report because for many comparisons or outcomes of interest no studies of better

methodological quality were available.

Three(41, 42, 44) of the nine included studies were sponsored by the pharmaceutical

industry; in one case(40) funding was not explicitly reported but the second author was

affiliated with the manufacturer of the study medications. The other five studies did not

report their funding source.(43, 45-48)

We included extended-release opioids administered orally or transdermally. Only two

medications, transdermal fentanyl and transdermal buprenorphine are available as

transdermal applications. For most comparisons of interest, we could not find any studies.

Out of 66 possible comparisons for the 12 included extended-release opioids, we found

studies for only nine head-to-head comparisons.

4.4 Key Question 1: Comparative Efficacy and Effectiveness of

Extended-Release Opioids

4.4.1 Description of Included Studies

Three studies met eligibility criteria for KQ1, the comparative efficacy and effectiveness of

extended-release opioids.(40-42) Table 7 summarizes the characteristics of the available

body of evidence for KQ1.


29

Table 7: Characteristics of the Available Evidence for KQ1.

Characteristic Details

N studies: (N patients) 3 studies (428 patients)

Range of means of age in studies: 56 – 61.68

Sex: N patients (%) Female Male

220 (51.4%) 208 (48.6%)

Race: N patients (%) White Non-white NR

407 (95%) 6 (1.5%) 15 (3.5%)

Setting: N studies Inpatients, outpatients and day patients NR

1 2

Risk of Bias: N studies (%) High Unclear Low

3 (100%) 0 0

Comparisons: N studies (N patients randomized) Oral morphine ER vs. oral hydromorphone ER Oral hydromorphone ER vs. oral oxycodone ER Oral oxycodone ER vs. oral oxycodone ER plus naloxone

1 (200) 1 (44) 1 (184)

Abbreviations: ER, extended-release; N, number;NR, not reported vs., versus.

All three studies were double-blind, head-to-head RCTs rated as high risk of bias.(40-42)

Table 8 summarizes the risk of bias ratings for included studies for KQ1. Reasons for high risk

of bias ratings are presented in Appendix D.

Table 8: Risk of Bias Summary for RCTs Included for KQ1.

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Hanna et al., 2008(42)

low risk of bias unclear risk of bias high risk of bias

- ? + + - + -

? ? + + - + -

+ ? + + - ? -

+ ? -


30

4.4.2 Key Points

Out of 66 possible comparisons of extended-release opioids, we found information on

the comparative efficacy for only three comparisons.

For patients with cancer pain, morphine ER and hydromorphone ER led to similar

improvements of pain intensity, quality of life, functional capacity, and cognitive

functioning (very low strength of evidence, one study).

For patients with stable cancer pain, hydromorphone ER and oxycodone ER led to similar

improvements of pain intensity (very low strength of evidence, one study).

For patients with moderate or severe chronic cancer pain, oxycodone ER and oxycodone

plus naloxone ER led to similar improvements of pain intensity and quality of life (very

low strength of evidence, one study each).

Patients treated with morphine ER, hydromorphone ER, oxycodone ER, and oxycodone

plus naloxone ER had similar discontinuation rates because of lack of efficacy (very low

strength of evidence, three studies).

We could not find any eligible head-to-head evidence on transdermal buprenorphine ER,

dihydrocodeine ER, transdermal fentanyl ER, morphine plus naltrexone ER, nalbuphine

ER, oxymorphone ER, tapentadol hydrochloride ER, and tramadol ER.

4.4.3 Detailed Synthesis

Table 9 summarizes the characteristics of included studies for KQ1.

Because results at cross-over were not reported in the publication by Hagen and Babul(40),

we contacted authors to release unpublished data. Authors provided us with results on pain

intensity as the only outcome for KQ1 which is presented below.


31

Table 9: Study Characteristics for all Studies Included for KQ1, the Investigated Outcomes and Risk of Bias Ratings.

Study and Study Design

Country and Setting

Funding N Comparison Outcomes of Interest Risk of Bias Rating

Ahmedzai et al., 2012(41) double-blind RCT

International (Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, United Kingdom), 64 study sites; setting NR

Mundipharma Research, Germany

184 Oral oxycodone ER vs. oral oxycodone plus naloxone ER

Pain intensity

Quality of life

High

Hagen and Babul, 1997(40) double-blind RCT

Canada; setting NR

NR 2

nd author

affiliated with Purdue Frederick, Canada (the producer of the study drugs)

44 Oral Hydromorphone ER vs. oral oxycodone ER

Pain intensity High

Hanna et al., 2008(42) double-blind RCT

International (Belgium, Canada, France, Germany, The Netherlands, Spain, Sweden, and the United Kingdom), 37 centres; inpatients, outpatients, and day patients

ALZA Corporation, USA

200 (IR phase) 163 (ER phase)

Oral morphine ER vs. oral hydromorphone ER

Pain intensity

Functional capacity

Quality of life

Patient perceived effectiveness

Cognitive performance

High

Abbreviations: ALZA, Alejandro Zaffaroni (portmanteau); IR, immediate-release; N, number of participants; NR, not reported; RCT, randomized controlled trial; vs., versus; ER, extended-release

In the following sections we present detailed analyses of head-to-head comparisons for each

outcome of interest. At the end of each outcome subchapter we summarize main results for

each outcome in a table. The order of the outcomes represents the importance of outcomes

as rated by our clinical experts – outcomes deemed to be critical for decision-making are

described first, followed by outcomes rated as important but not critical.

4.4.3.1 Pain Intensity

All three studies included for KQ1 assessed pain intensity.(40-42) Detailed results on pain

intensity are presented in Table 10.

http://en.wikipedia.org/wiki/Alejandro_Zaffaroni

http://en.wikipedia.org/wiki/Portmanteau


32

Oral Morphine ER vs. Oral Hydromorphone ER

The only available evidence for this comparison was a double-blind head-to-head RCT by

Hanna et al.(42) We rated the study as high risk of bias because of an attrition rate of 34%.

Because the article reported only dosing ranges, we were unable to assess the dosing

equivalence. The study was sponsored by Alejandro Zaffaroni (ALZA) Corporation, a

producer of hydromorphone ER. Two hundred patients were initially randomized to

immediate-release (IR) morphine (n=101) or immediate-release hydromorphone (n=99).

Eighty-six patients completed the morphine IR phase and were then switched to morphine

ER. Seventy-seven patients completed the hydromorphone IR phase and then began taking

hydromorphone ER. The attrition rate because of lack of efficacy during the ER phase was

3.5% in the morphine ER group and 6.5% in the hydromorphone ER group.

During the extended-release phase, patients on both medications achieved a decrease in

pain intensity. The decrease in pain intensity was numerically smaller for patients treated

with morphine ER (decrease from 4.8 to 4.3 points) than hydromorphone ER (decrease from

5.0 to 3.5 points; p=NR) with respect to worst pain in the past 24 hours. Decreases were

similar between drugs for current pain in the morning (morphine ER: decrease from 3.4 to

2.8 points; hydromorphone ER: decrease from 3.3 to 2.4 points) and current pain in the

afternoon (morphine ER: decrease from 3.7 to 3.4 points; hydromorphone ER: decrease

from 3.6 to 2.6 points; p=NR, see Table 10). Both outcomes were measured on an 11-point

Brief Pain Inventory (BPI)-scale (0=no pain, 10=pain as bad as you can imagine). Differences,

however, did not reach statistical significance. Results of two other pain scales (least pain in

the last 24 hours and average pain in the last 24 hours (see Table 10) were also similar for

both study groups.

Because of methodological limitations, imprecision of results, and the fact that only a single

study assessed this outcome, the strength of evidence that morphine ER and

hydromorphone ER are equally efficacious with respect to pain intensity is very low (see

Appendix-Table 3).

Oral Hydromorphone ER vs. Oral Oxycodone ER

One study met our eligibility criteria for this comparison – a high risk of bias RCT(40) (n=44)

comparing the efficacy of hydromorphone ER with oxycodone ER during a study period of

http://en.wikipedia.org/wiki/Alejandro_Zaffaroni


33

seven days. Funding of this study was not reported but one author had an affiliation with the

producer of both study medications. The study employed a cross-over design; in the

following section we report comparisons of the two drugs before cross-over. The study was

rated as high risk of bias because of an attrition rate of 30% and a lack of ITT-analysis.

Results showed a numerically smaller reduction in pain intensity measured on a 100mm

visual analog scale (VAS) with hydromorphone ER compared with oxycodone ER after seven

days of treatment (difference of 4.3 mm; p=NR, see Table 10). When pain intensity was

measured with an ordinal scale (0=none, 1=mild, 2=moderate, 3=severe, 4=excruciating

pain), no difference in reduction of pain intensity between the groups was found (see Table

10). Results, however, have to be interpreted cautiously because the mean morphine-dose-

equivalent of oxycodone ER (124 mg/d) was 50% higher than that of hydromorphone ER (30

mg/d). The higher mean dosage for patients on oxycodone ER can partly be explained by a

higher mean pain score at baseline compared with patients on hydromorphone ER

(33.28mm vs. 27.87mm).


study assessed this outcome, the strength of evidence that hydromorphone ER and

oxycodone ER are equally efficacious with respect to pain intensity is very low (see

Appendix-Table 4).

Oral Oxycodone ER vs. Oral Oxycodone plus Naloxone ER


Ahmedzai et al.with a high risk of bias.(41) This study investigated the comparative efficacy

and risk of harms of oxycodone ER and oxycodone plus naloxone ER in 184 patients with

chronic moderate or severe cancer pain. Because of lack of information, we were unable to

assess the dosing equivalence of drugs in this study. Findings showed similar changes in pain

scores after four weeks as measured on an 11-point BPI (oxycodone ER: decrease from 4.18

to 3.52 points, oxycodone plus naloxone ER: decrease from 4.16 to 3.50; p=NR) (see Table

10). The study was funded by Mundipharma Research, the producer of oxycodone plus

naloxone ER. This RCT was rated as high risk of bias because of the use of a pseudo-random

number generator for randomization, per-protocol analysis for some of the outcomes, and a

high attrition rate (28%).


34


study assessed this outcome, the strength of evidence that oxycodone ER and oxycodone

plus naloxone ER are equally efficacious with respect to pain intensity is very low (see

Appendix-Table 5).


35

Table 10: Study Characteristics and Summary of Findings on Pain Intensity.

Study N Duration Comparison and Dose

Outcome Measure Pain Intensity Risk of Bias



200 (IR phase) 163 (SR phase)

10-15 days

Morphine ER: 60-540 mg/d

Hydromorphone ER: 16-96 mg/d

BPI for worst pain in the past 24h (0=no pain, 10=pain as bad as you can imagine)

Similar reduction of pain intensity for worst pain in the past 24h with morphine ER; Mean score change: morphine ER:- 0.5, hydromorphone ER: -1.5; p=NR

High

BPI for least pain in the past 24h Similar changes for least pain in the past 24h; Mean score change: morphine ER: -0.4, hydromorphone ER: 0; p=NR

BPI for average pain in the past 24h Similar changes for average pain in the past 24h with both study drugs; Mean score change: morphine ER: -0.4, hydromorphone ER: -0.2; p=NR

BPI for current pain (AM/PM) Similar reduction of current pain AM/PM with morphine ER; Mean score change (pain now AM/PM): morphine ER: -0.6/-0.3 hydromorphone ER: -0.9/-1; p=NR



44 7 days Hydromorphone ER: mean final dose 30 ± 6 mg/d Oxycodone ER: 124 ± 22 mg/d

Pain intensity VAS 0-100mm (0=no pain, 100=excruciating pain)

Less reduction of pain intensity with hydromorphone ER Mean score change: hydromorphone ER: -2.38, oxycodone ER: -6.70; p=NR

High

Ordinal pain scale (0=none, 1=mild, 2=moderate, 3=severe, 4=excruciating)

Similar reduction in pain intensity with both study drugs Mean score change: hydromorphone ER: -0.25, oxycodone ER: -0.24; p=NR


36


Outcome Measure Pain Intensity Risk of Bias



184 4 weeks Oxycodone ER: mean 43.09 (SD 19.31) mg/d Oxycodone plus naloxone ER: 46.59 (SD 22.58) mg/d

BPI-SF questionnaire (0=no pain, 10=pain as bad as you can imagine)

Similar pain scores at baseline and at 4 weeks in both study groups; Mean score change: Oxycodone ER: -0.66 Oxycodone plus naloxone ER: -0.66, p=NR

High

Abbreviations : AM, ante meridiem (meaning before midday); BPI, brief pain inventory; BPI-SF, Brief Pain Inventory-Short form; d, day; ER, extended-release; h, hour; IR, immediate-release; mg, milligram; mm, millimeter; N, number of participants; NR, not reported; p, probability; PM, post meridiem (meaning after midday); SD, standard deviation; SR, sustained-release; VAS, visual analogue scale; vs., versus; μg, microgram.


37

4.4.3.2 Quality of Life

Among the three studies analysed for KQ1, two head-to-head trials provided data on quality

of life.(41, 42) Table 11 summarizes results of the included studies.


The only available evidence for this comparison was the double-blind, high risk of bias head-

to-head trial (n= 200) by Hanna et al.(42) which has been described in detail above (within

the section on pain intensity). Quality of life was measured with a BPI interference scale for

enjoyment of life. Results showed similar improvements in quality of life scores between

patients treated with morphine ER (decrease from 3.9 to 3.5 points; p=NR) and

hydromorphone ER (decrease from 4.1 to 3.5 points; p=NR). BPI score changes for

relationship (0.1 vs. 0.2 points; p=NR) and mood (0.2 vs. 0.2 points; p=NR) were also similar

between groups (see Table 11).

Because of methodological limitations, imprecision of results and the fact that only a single


hydromorphone ER are equally efficacious with respect to quality of life is very low (see

Appendix-Table 3).


Only one study met our eligibility criteria for this comparison.(41) This high risk of bias RCT

(n=184) by Ahmedzai et al. has been described in more detail in the section on pain

intensity. After four weeks of treatment, patients in both treatment groups reported similar

quality of life scores on the European Quality of Life Instrument (EuroQoL EQ-5D) (0.49 vs.

0.50; p=NR, Table 11).

Because of methodological limitations, imprecision of results and the fact that only a single


plus naloxone ER are equally efficacious with respect to quality of life is very low (see

Appendix-Table 5).


38

Table 11: Study Characteristics and Summary of Findings on Quality Of Life.


Outcome Measure

Quality of Life Risk of Bias




10-15 days

Morphine ER: 60-540 mg/d vs. Hydromorphone ER: 16.96 mg/d

BPI interference scale for enjoyment of life (0=no interference, 10=complete interference)

Similar improvement for enjoyment of life with both study drugs: Mean score change morphine ER: -0.4, hydromorphone ER: -0.6; p=NR

High/

BPI interference scale for relationships

Similar results for relationships with both study drugs: Mean score change morphine ER: 0.1, hydromorphone ER: 0.2; p=NR

BPI interference scale for mood

Similar slight improvement for mood with both study drugs: Mean score change morphine ER: -0.2, hydromorphone ER: - 0.2; p=NR




EuroQoL EQ-5D Similar QoL scores at baseline and at 4 weeks in both study groups: Mean score at endpoint oxycodone ER: 0.49, oxycodone plus naloxone ER: 0.50; p=NR

High

Abbreviations : BPI, brief pain inventory; d, day; ER, extended-release; EuroQoL EQ-5D, European Quality of Life instrument; IR, immediate-release; mg, milligram; N, number of participants; NR, not reported; p, probability; QoL, quality of life; SD, standard deviation; SR, sustained-release; vs., versus.

4.4.3.3 Functional Capacity

Among the three studies analysed for KQ1 only one study reported information on

functional capacity (see Table 12).(42)


The only available evidence for this comparison was a two-phase (IR phase and ER phase)

RCT (n=200) determining the equivalency of morphine ER and hydromorphone ER.(42)


39

Details of this study by Hanna et al. have been described above in the section on pain

intensity. Results presented a similar improvement of general activity (BPI interference scale

for general activity) in patients treated with morphine ER (decrease from 4.3 to 4.1 points; p

= NR) or hydromorphone ER (decrease from 4.2 to 3.7 points; p=NR).



hydromorphone ER are equally efficacious with respect to functional capacity is very low.

Table 12: Study Characteristics and Summary of Findings on Functional Capacity.

Study N Duration Comparison and dose

Outcome measure Functional capacity

Risk of bias




10-15 days

Morphine ER: 60-540 mg/d Hydromorphone ER: 16-96 mg/d

Brief Pain Inventory interference scale for general activity (0=no interference, 10=complete interference)

Similar improvement for general activity with both study drugs: Mean score change morphine ER: -0.2, hydromorphone ER: -0.5; p=NR

High

Abbreviations: d, day; ER, extended-release; IR, immediate-release; mg, milligram; N, number of participants; NR, not reported; p, probability; SR, sustained-release.

4.4.3.4 Patient Perceived Effectiveness

Among the three studies analysed for KQ1 only one study reported information on patient

perceived effectiveness, which means patients’ global assessments of treatment

effectiveness as good, very good, or excellent. Table 13 presents results for patient

perceived effectiveness.



Hanna et al. (42) with a high risk of bias, described in detail in the section on pain intensity.

At the end of the 10-15 days ER-phase numerically more patients (80.2%) in the morphine ER

group than in the hydromorphone ER group (73.4%) rated the treatment as good, very good

or excellent (p=NR). This outcome was measured on a 5-point scale (1=poor, 2=fair, 3=good,

4=very good, 5=excellent). Using the data from the study we calculated a statistically not


40

significant difference between the two treatment groups (Odds ratio [OR]: 1.42, 95% CI 0.68-

2.97)



hydromorphone ER are equally efficacious with respect to perceived effectiveness is very

low (see Appendix-Table 3).

Table 13: Study Characteristics and Summary of Findings on Patient Perceived Effectiveness.


Outcome Measure

Evaluation of Treatment

Risk of Bias




10-15 days


5-point scale (1=poor, 2=fair, 3=good, 4=very good, 5=excellent)

80.2% of participants in the morphine ER group and 73.4% in the hydromorphone ER group rated the treatment as good, very good or excellent (p=NR)

High

Abbreviations: d, day; ER, extended-release; IR, immediate-release; mg, milligram; N, number of participants; NR, not reported; p, probability; SR, sustained-release.

4.4.3.5 Cognitive Performance

Among the three studies analysed for KQ1, only one high risk of bias RCT reported on

cognitive performance associated with the use of extended-release opioids.(42) Table 14

presents the results for the outcome cognitive performance.


The only available evidence for this comparison was the high risk of bias head-to-head trial

by Hanna et al.(42) which has been described in more detail in the section on pain intensity.

The Mini-Mental State Examination scores for measuring cognitive performance of 200

participants revealed similar scores between the two treatment groups at endpoint (29.2 vs.

28.9; p=NR), with a small identical decline of scores (0.4 points) from baseline to endpoint in

both groups (see Table 14).


41

Table 14: Study Characteristics and Summary of Findings on Cognitive Performance.


Outcome Measure

Cognitive Performance

Risk of Bias




10-15 days


MMSE scores (0-30); higher scores indicate better cognitive performance

Similar scores at endpoint: 29.2 vs. 28.9, p=NR

High

Abbreviations: d, day; ER, extended-release; IR, immediate-release; mg, milligram; MMSE, Mini-Mental State Examination; N, number of participants; NR, not reported; p, probability; vs., versus.

4.4.3.6 Discontinuation Due to Lack of Efficacy

The rate of discontinuation due to lack of efficacy was similar among drugs and ranged from

1.1% (oxycodone plus naloxone ER) to 6.5% (hydromorphone ER). Nevertheless, because of

small sample sizes, differences among drugs have to be interpreted cautiously.

Table 15 presents rates of discontinuation due to lack of efficacy for the included double-

blind head-to-head studies for the comparative efficacy and effectiveness of extended-

release opioids.

Table 15: Rates of Discontinuation Due to Lack of Efficacy by Study Drug.

Study N per Drug Discontinuation Due to Lack of Efficacy (N)

Discontinuation Due to Lack of Efficacy (%)

Oral Morphine ER

Hanna et al., 2008(42) 86* 3 3.5

Oral Hydromorphone ER

Hagen and Babul, 1997(40) 19 NR NR

Hanna et al., 2008(42) 77* 5 6.5

Oral Oxycodone ER

Ahmedzai et al., 2012(41) 92 4 4.3

Hagen and Babul, 1997(40) 12** NR NR

Oral Oxycodone plus Naloxone ER

Ahmedzai et al., 2012(41) 92 1 1.1

* only phase II with ER medication ** only first phase before cross-over; three patients discontinued due to inadequate pain control from the whole populationAbbreviations: ER, extended-release; N, number of participants; NR, not reported.


42

4.5 Key Question 2: Comparative Risk of Harms of Extended-

Release Opioids

This chapter is structured as follows: First, we discuss general results of the literature

searches and characteristics of included studies. Next, we present key points followed by a

detailed synthesis of the available evidence. The detailed synthesis is structured by adverse

events:

Serious adverse events (section 4.5.3.1)

Discontinuation rates and overall tolerability (section Discontinuation Rates and

Overall Tolerability4.5.3.2)

Constipation (section 4.5.3.3)

Nausea and vomiting (section 4.5.3.4)

Dizziness (section 4.5.3.5)

Drowsiness, Somnolence, Fatigue, Sedation (section 4.5.3.6)

Diarrhea (section 4.5.3.7)

4.5.1 Description of Included Studies

Overall, nine studies with more than 2600 patients provided data on the assessment of

adverse events of extended-release opioids.(40-48). Table 16 summarizes the characteristics

of the available body of evidence for KQ2.


43

Table 16: Characteristics of the Available Evidence for KQ2.

Characteristic Details N Studies: (N patients) 9 studies (2663 patients)

Range of means of age in studies: 52.8 – 67.8

Sex: N patients (%) Female Male

1411 (53.0%) 1252 (47.0%)

Race: N patients (%) White Non-white NR

1559 (58.5%) 120 (4.5%) 984 (37.0%)

Setting: N studies (%) Inpatients, outpatients and day patients NR

7 (78%) 2 (22%)

Risk of Bias: N studies (%) High Unclear Low

6 (67%) 3 (33%) 0

Comparisons: N studies (N patients randomized) Oral morphine ER vs. oral hydromorphone ER Oral morphine ER vs. oral oxycodone ER Oral morphine ER vs. transdermal fentanyl ER Oral hydromorphone ER vs. oral oxycodone ER Oral hydromorphone ER vs. transdermal fentanyl ER Oral hydromorphone ER vs. transdermal buprenorphine ER Oral oxycodone ER vs. oral oxycodone + naloxone ER Oral oxycodone ER vs. transdermal fentanyl ER Transdermal fentanyl ER vs. transdermal buprenorphine ER

2 (302) 2 (1072) 4 (1198) 1 (44) 1 (124) 1 (124) 1 (184) 2 (993) 1 (124)

Abbreviations: ER, extended-release; N, number; NR, not reported; vs, versus.

In addition to the three RCTs that we included for comparative efficacy in KQ1(40-42), two

RCTs(43, 44) and four observational studies(45-48) met our eligibility criteria for the

assessment of the risk of harms. The risk of bias summaries of the five RCTs included for KQ2

are presented in Table 17. The risk of bias summaries for observational studies included for

KQ2 are presented in Table 18.


44

Table 17: Risk of Bias Summaries for RCTs Included for KQ2.

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van Seventer et al., 2003(44)


Table 18: Risk of Bias Summary for Observational Studies Included for KQ2.

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+ ? - -


45

4.5.2 Key Points

Out of 66 possible comparisons of extended-release opioids, we found information on the

comparative risk of harms for only nine comparisons.

For patients with cancer pain, available evidence indicates a similar risk of serious

adverse events among compared drugs:

o Morphine ER versus hydromorphone ER (very low strength of evidence, one

study)

o Morphine ER versus oxycodone ER (very low strength of evidence, one study)

o Morphine ER versus transdermal fentanyl ER (low strength of evidence, two

studies)

o Oxycodone ER versus oxycodone plus naloxone ER (very low strength of

evidence, one study)

The risk of constipation was similar amongst most compared drugs:

o Morphine ER versus hydromorphone ER (very low strength of evidence, one

study)

o Morphine ER versus oxycodone ER (very low strength of evidence, one study)

o Morphine ER versus transdermal fentanyl ER (low strength of evidence, three

studies)

o Hydromorphone ER versus transdermal fentanyl ER (very low strength of


o Hydromorphone ER versus transdermal buprenorphine ER (very low strength

of evidence, one study)

o Transdermal fentanyl ER versus transdermal buprenorphine ER (very low

strength of evidence, one study)

Oxycodone plus naloxone ER had a lower risk of constipation than oxycodone ER (low


The risk for nausea and vomiting was similar amongst most compared drugs:

o Morphine ER versus transdermal fentanyl ER (very low strength of evidence,

three studies)

o Hydromorphone ER versus oxycodone ER (very low strength of evidence, one

study)


46

o Oxycodone ER versus oxycodone plus naloxone ER (very low strength of


o Transdermal fentanyl versus transdermal buprenorphine (very low strength of


Morphine ER had a higher risk of nausea and vomiting than hydromorphone ER (very

low strength of evidence, two studies)

Morphine ER had a lower risk of nausea than oxycodone ER (very low strength of


Hydromorphone ER had a similar risk of nausea but a higher risk of vomiting than

transdermal fentanyl ER (very low strength of evidence, one study) or transdermal

buprenophine ER (very low strength of evidence, one study)

Oxycodone ER had a higher risk of nausea than transdermal fentanyl ER (very low


4.5.3 Detailed Synthesis

Table 19 summarizes characteristics of studies included for KQ2. In the following sections we

summarize results first on serious adverse events, second on discontinuation rates and

general tolerability, and third on the comparative risk of specific adverse events. Within each

section, we discuss findings by drug to drug comparisons.


47

Table 19: Study Characteristics for all Studies Included for KQ2, the Investigated Outcomes and Risk of Bias Ratings.

Study and Study Design Country and Setting Funding N Comparison Outcomes of Interest Risk of Bias Rating

Ahmedzai et al., 2012(41) double-blind RCT

International (Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, United Kingdom), 64 study sites; setting NR

Mundipharma Research, Germany

184 Oral oxycodone ER vs. oral oxycodone ER plus naloxone

Nausea

Vomiting

Constipation

High

Hagen and Babul, 1997(40) double-blind RCT

Canada; setting NR

NR 2

nd author affiliated

with Purdue Frederick, Canada (the producer of the study drugs)

44 Oral hydromorphone ER vs. oral oxycodone ER

Nausea

Somnolence

High

Hanna et al., 2008(42) double-blind RCT

International (Belgium, Canada, France, Germany, The Netherlands, Spain, Sweden, and the United Kingdom), 37 centres; inpatients, outpatients, and day patients

ALZA Corporation, USA 200 (IR phase) 163 (ER phase)

Oral morphine ER vs. oral hydromorphone ER

Nausea

Vomiting

Constipation

Somnolence

Dizziness

Fatigue

High

Hartung et al., 2007(48) retrospective cohort study

USA, State Oregon fee-for-service recipients; Setting NR

NR 1295 Oral morphine ER vs. oral oxycodone ER vs. transdermal fentanyl ER

ED/hospitalization

Mortality

ED encounters

Hospitalization

Opioid poisoning

Overdose symptoms

Constipation (ED or hospital encounters for constipation)

Unclear

Mercadante et al., 2008(43) non-blinded RCT

Italy, multicenter study; setting NR

NR 108 Oral morphine ER vs. transdermal fentanyl ER

Constipation

Nausea/vomiting

Drowsiness

Confusion

High


48

Study and Study Design Country and Setting Funding N Comparison Outcomes of Interest Risk of Bias Rating

Okamoto et al., 2010(47) retrospective cohort study

Japan; hospital information system of the Osaka University Hospital

NR 413 Oral morphine ER vs. oral oxycodone ER vs. transdermal fentanyl ER

Nausea

Somnolence

High

van Seventer et al., 2003(44) non-blinded RCT

The Netherlands, multicentre Study (26 sites); setting NR

The Netherlands, Janssen-Cilag BV

131 Oral morphine ER vs. transdermal fentanyl ER

Nausea

Vomiting

Constipation

Daytime drowsiness

Daytime sleepiness

Respiratory depression

High

Wirz et al., 2008(45) prospective cohort study

Germany; ambulatory pain clinic

NR 102 Oral morphine ER vs. oral hydromorphone ER

Nausea

Vomiting

Constipation

Unclear

Wirz et al., 2009 (46) prospective cohort study

Germany; ambulatory pain clinic

NR 186 Oral hydromorphone ER vs. transdermal fentanyl ER vs. transdermal buprenorphine ER

Nausea

Vomiting

Constipation

Unclear

Abbreviations: ED, emergency department; ER, extended-release; IR, immediate-release; n, study participants; NR, not reported; RCT, randomized controlled trial; vs., versus.


49

4.5.3.1 Serious Adverse Events

The FDA defines a serious adverse event (SAE) in human drug trials as an undesirable

occurrence caused by any dose of a study treatment resulting in death, a threat to life,

hospitalization or prolongation of hospitalization, persistent or clinically significant

incapacity, substantial disruption of the ability to conduct normal life functions, or a

congenital anomaly or birth defect.(49) Similarily, the EMA defines a serious adverse event

as any untoward medical occurrence that at any dose: (1) results in death; (2) is life-

threatening; (3) requires inpatient hospitalisation or prolongation of existing hospitalisation;

(4) results in persistent or significant disability/incapacity; or (5) is a congenital

anomaly/birth defect.(50) To identify potential SAEs, we initially tried to use FDA and EMA

definitions. Unfortunately, SAEs in studies were either not clearly defined or definitions were

not in line with those of the FDA or EMA.As a result, we had to rely on guidance from a

clinical practitioner to determine which SAEs to report on. The practitioner recommended

reporting adverse events that led to hospital admission or prolongation of hospitalization

(e.g., due to severe dizziness, nausea, vomiting and constipation).

Less than half of our included studies reported on SAEs related to extended-release opioids

(SAEs such as death were often reported to have been caused by the progression of cancer

and not attributed to opioid treatment for pain). Overall, four studies with data on 1700

patients provided information on SAEs, including: death due to overdose, opioid poisoning,

hospitalization, and respiratory failure.(41, 42, 44, 48) However, data was often not clearly

presented and specific SAEs were rarely reported, which made comparisons of SAEs by

treatment difficult.

4.5.3.1.1 General Risk of Serious Adverse Events

Overall, the risk of SAEs (as reported by study authors) varied from 4.3% for oxycodone

ER(41) to 38% for morphine ER (9% due to progression of the underlying disease).(44) Table

20 summarizes frequencies of SAEs for extended-release opioids. Because definitions of SAEs

varied greatly among studies, frequencies cannot be compared across drugs.


50

Table 20: Reported Frequencies of Serious Adverse Events by Drug.

Generic name Frequency of serious adverse events

Transdermal Buprenorphine ER No data

Dihydrocodeine ER No data

Transdermal Fentanyl ER 30% (thereof 9% due to disease progression)

Hydromorphone ER 16%

Morphine ER 16% - 38% (thereof 9% due to disease progression)

Morphine + Naltrexone ER No data

Nalbuphine ER No data

Oxycodone ER 4.3%

Oxycodone + Naloxone ER 8.7%

Oxymorphone ER No data

Tapentadol hydrochloride ER No data

Tramadol ER No data Abbreviations: ER, extended-release.

4.5.3.1.2 Comparative Risk of Serious Adverse Events

Four studies provided data on the comparative risk of SAEs.(41, 42, 44, 48) Table 21

summarizes findings of these studies.


In one high risk of bias study with two phases (IR phase, n=200 and ER phase, n=163),

patients were randomized to receive morphine ER or hydromorphone ER during 10-15

days.(42) Because the article reported only dosing ranges, we were unable to assess the

dosing equivalence. Overall, 12% (24/200) of patients experienced at least one SAE. The risk

of experiencing an SAE was similar between treatment groups. In the ER phase 10.5% (9/86)

of patients in the morphine ER group reported an SAE compared with 9% (7/77) in the

hydromorphone ER group. Authors reported that many of the SAEs were associated with the

underlying disease and that one-third were considered definitely or probably related to the

study therapy (n not reported). The study disclosed neither the nature of the SAEs nor the

definitions used for SAE classification. Therefore, we are unable to ascertain if the SAEs met

our criteria. Due to the limited evidence available, no inferences can be made about

differences between the two drugs in opioid-induced SAEs.



hydromorphone ER have a similar risk for SAEs is very low (see Appendix-Table 6).


51

Oral Morphine ER vs. Oral Oxycodone ER

A retrospective cohort study (n=810), with an unclear risk of bias, reported hazard ratios

(HR) for cancer patients who experienced opioid poisoning or who were admitted to the

hospital due to SAEs associated with the intake of morphine ER or oxycodone ER.(48) The HR

for the risk of hospital admission was adjusted for constipation, alteration of consciousness,

malaise, fatigue, lethargy, respiratory failure, and opioid poisoning. The drug dosages were

equivalent between morphine ER and oxycodone ER.

Morphine ER had a similar risk for hospital admissions due to SAEs compared with

oxycodone ER (HR 1.47, 95% CI: 0.58-3.7, p=0.411). Likewise, the risks for opioid poisoning

(HR 2.43, 95% CI: 0.12-50.0) and overdose symptoms (HR 0.95, 95% CI: 0.63-1.45) were not

statistically significantly different between morphine ER and oxycodone ER. Overdose

symptoms were summarized for alteration of consciousness, malaise, fatigue, lethargy and

respiratory failure. Confidence intervals of all estimates, however, are wide and encompass

differences that would be clinically meaningful. For example the risk for hospital admissions

due to SAEs comprises differences from a 42% lower to a 370% higher risk of oxycodone ER

than morphine ER. (HR 1.47, 95% CI 0.58-3.7, p=0.411) Therefore, findings should be viewed

as indeterminate.


study assessed this outcome, the strength of evidence that morphine ER and oxycodone ER

have a similar risk for opioid poisoning and hospital admission due to SAEs is very low (see

Appendix-Table 7).

Oral Morphine ER vs. Transdermal Fentanyl ER

A retrospective study (n=778)(48) with an unclear risk of bias and a high risk of bias RCT

(n=131)(44) described the risk of SAEs associated with the intake of morphine ER and

transdermal fentanyl ER. Both studies reported no statistically significant differences for the

risk of SAEs between morphine ER and transdermal fentanyl ER.

The retrospective study, described in the previous chapter, reported a similar risk for

hospital admissions due to SAEs of morphine ER (n=471) compared to transdermal fentanyl

ER (n=307): HR 0.93, 95% CI 0.36-2.33.(48) The hazard ratio for the risk of hospital admission


52

was adjusted for constipation, alteration of consciousness, malaise, fatigue, lethargy,

respiratory failure and opioid poisoning. The risk for overdose symptoms was also similar

between morphine ER and transdermal fentanyl ER (HR 0.95, 95% CI: 0.63-1.45). Overdose

symptoms were summarized for alteration of consciousness, malaise, fatigue, lethargy and

respiratory failure. The morphine-equivalent dose of transdermal fentanyl ER was 20%

higher than the morphine ER dose. Confidence intervals of all estimates, however, are wide

and encompass differences that would be clinically meaningful. The study was funded by

Janssen Cilag, the producer of a transdermal fentanyl patch.

The high risk of bias RCT reported 38% (24/64) SAEs in the morphine ER group and 30%

(20/67) SAEs in the transdermal fentanyl ER group.(44) The difference was not statistically

significant (OR 1.41, 95% CI: 0.68-2.92). For approximately 50% of the SAEs, specific reasons

were reported: in both treatment groups 9% of the SAEs were due to disease progression (6

patients in each treatment group) and 5-6% due to dyspnoea (morphine ER: 3/64,

transdermal fentanyl ER: 4/67). Both studies revealed no statistically significant difference

between morphine ER and transdermal fentanyl ER. However, due to the wide confidence

intervals of all estimates, reported findings should be viewed as indeterminate.

Because of methodological limitations and imprecision of results, the strength of evidence

that morphine ER and transdermal fentanyl ER have a similar risk of SAEs is low (see

Appendix-Table 8).

Oral Oxycodone ER vs. Oral Oxycodone ER plus Naloxone

Another RCT, rated as having a high risk of bias, reported numerically lower rates of SAEs for

oxycodone ER (4.3%) than oxycodone ER plus naloxone (8.7%).(41) Dosages were equivalent

between drugs. The difference, however was not statistically significant (OR 0.48; 95% CI:

0.14-1.64) No further information about the nature or the definition which lead to the

classification of SAEs was reported. The study was funded by Mundipharma, the producer of

the oxycodone ER plus naloxone combination drug. Due to the wide confidence interval and

an overall lack of available evidence, the comparative risk of SAEs between oral oxycodone

ER and oral oxycodone ER plus naloxone is indeterminate.


53



plus naloxone ER have a similar risk for SAEs is very low (see Appendix-Table 12).


54

Table 21: Study Characteristics and Summary of Findings on Serious Adverse Events.

Study N Duration Comparison and Dose Outcome Measure Serious Adverse Events Risk of Bias




10-15 days Morphine ER: 60-540 mg/d hydromorphine ER: 16-96 mg/d

SAE (not specified) Overall: 12% (24/200): IR-phase: 5 patients in each treatment group, ER-phase: morphine ER: 10.5% (9/86), hydromorphone ER: 9% (7/77) Many of the SAE were associated with the underlying disease: 1/3 were considered definitely or probably related to the study therapy

High



810 NR Morphine ER: mean±SD 85.1±60.0 mg/d oxycodone ER: morphine equivalent dose: 75.47±58.7 mg/d

ED encounters and hospitalization for constipation, alteration of consciousness, malaise, fatigue, lethargy, respiratory failure, opioid poisoning

Similar risk for ED encounters or hospital encounters (*HR 1.47, 95% CI: 0.58-3.7)

Unclear

Opioid poisoning Similar risk for opioid poisoning (*HR 2.43, 95% CI: 0.12-50.0)

Overdose symptoms (alteration of consciousness, malaise, fatigue, lethargy, respiratory failure)

Similar risk for overdose symptoms (*HR 0.95, 95% CI: 0.63-1.45)



55

Study N Duration Comparison and Dose Outcome Measure Serious Adverse Events Risk of Bias


778 NR Morphine ER: mean±SD 85.1±60.0 mg/d Transdermal fentanyl ER: morphine equivalent dose 102.76±90.0 mg/d

ED encounters and hospitalization for constipation, alteration of consciousness, malaise, fatigue, lethargy, respiratory failure, opioid poisoning

Similar risk for ED encounters or hospital encounters (*HR 0.93, 95% CI: 0.36-2.33)

Unclear

Overdose symptoms (alteration of consciousness, malaise, fatigue, lethargy, respiratory failure)

Similar risk for overdose symptoms (*HR 0.95, 95% CI: 0.63-1.45)


131 4 weeks Morphine ER: start 30 mg/12 h, max. average dose 105 mg/24 h transdermal fentanyl ER: start 25 µg/72 h, max. average dose 67 µg/72 h

SAEs as defined by authors of study: disease progression (6 per group), dyspnoea (morphine ER: 3, transdermal fentanyl ER: 4), vomiting (morphine ER: 5, transdermal fentanyl ER: 0 )

No statistically significantly different risk for SAEs: morphine ER: 38% (24/64), transdermal fentanyl ER: 30% (20/67), *OR 1.41 (95% CI: 0.68-2.92)

High



184 4 weeks Oxycodone ER: mean 43.09 (SD 19.31) mg/d oxycodone plus naloxone ER: 46.59 (SD 22.58) mg/d

SAE (not specified) No statistically different risk for SAE: oxycodone ER: 4.3% (4/92), oxycodone ER/naloxone: 8.7% (8/92) *OR 0.48 (95% CI: 0.14-1.64)

High

*internal calculations based on the available data

Abbreviations: CI, confidence interval; d, Day; ED, emergency department; ER, extended-release; h, hours; HR, hazard ratio; IR, immediate-release; mg, milligram; n, study participants; NR, not reported; OR, odds ratio; SAE, serious adverse event; SD, standard deviation; vs., versus; μg, microgram.


56

4.5.3.2 Discontinuation Rates and Overall Tolerability

The most common adverse events reported were constipation, nausea, vomiting, and

somnolence. If sufficient data were available, we calculated the weighted mean and 95%

confidence intervals from efficacy trials and observational studies to investigate the overall

discontinuation rates, discontinuation rates because of adverse events, and the mean

incidence of specific adverse events (Table 22). Discontinuation rates due to lack of efficacy

are presented in Table 15 (see chapter 4.4.3.6). Statistics are descriptive only and

comparisons across different drugs should not be made because of the small number of

included studies and the differences in reporting and assessing of adverse events across

studies.

The mean discontinuation rates because of adverse events for specific drugs vary between

4% (95% CI: 0%-9%) for patients treated with transdermal fentanyl ER and 22% (95% CI: 13%-

30%) for patients treated with oral oxycodone ER plus naloxone. We did not have any data

about discontinuation rates for morphine ER, dihydrocodeine ER, morphine ER plus

naltrexone, nalbuphine ER, oxymorphone ER, transdermal buprenorphine ER and tramadol

ER.

Overall, extended-release opioids led to a similar spectrum of adverse events. Results in

Table 22 are descriptive only and cannot prove a higher risk of a specific adverse event for a

particular drug over another.


57

Table 22: Drop-Out Rates and Risk for Specific Adverse Events During the Stable Phase of Treatment.

Drug Overall drop-out rate (% and 95% CI)

Drop out because of adverse events (% and 95% CI)

Constipation (% and 95% CI)

Vomiting (% and 95% CI)

Nausea (% and 95% CI)

Somnolence (% and 95% CI)


Insufficient data**

Insufficient data**

21 (11-32)* 13 (5-22) * Insufficient data**

Insufficient data**


30 (0-80) 4 (0-9)* 20 (0-44) Insufficient data**

Insufficient data**

Insufficient data**

Hydromorphone ER 22 (13-31)*

8 (2-14)*

18 (0-72) 24 (0-75) 19 (11-28)* 10 (4-17)*

Morphine ER Insufficient data**

Insufficient data**

23 (9-36) 27 (14-40) 31 (9-53) 26 (0-58)

Oxycodone ER 27 (18-36)*

13 (6-20)* 7 (1-12)

5 (1-10)* Insufficient data**

Insufficient data**

Oxycodone ER plus naloxone

28 (19-37)*

22 (13-30)* 7 (1-12)* 7 (1-12)* 8 (2-13)* Insufficient data**

*Estimate based on a single study **Insufficient data due to lack of studies or wide and inconclusive confidence intervals Abbreviations: CI, confidence interval; ER, extended-release.

4.5.3.3 Constipation

Overall, seven studies reported on the risk of constipation associated with the intake of

extended-release opioids.(41-46, 48) Detailed findings are presented in Table 23. The

weighted means of the incidence of constipation of the included drugs ranged from 7% to

23%.


For this comparison we included one prospective controlled cohort study designed to

investigate adverse events of extended-release opioids(45), rated as unclear risk of bias and

one head-to-head RCT(42), rated as high risk of bias. Overall, results of the two studies with

data on more than 260 patients were conflicting.

A prospective controlled cohort study(45) randomly selected outpatients of a cancer-pain

clinic who had been on opioid therapy for more than 28 days. The dosages of patients

treated with hydromorphone ER was 45% to 100% higher than the dosage of patients

treated with morphine ER. A comparison of 100 patients showed similar constipation rates

in three out of four outcomes (see Table 22) Only, the number of patients with stool free

interval >72 h was higher in the morphine ER group than in the hydromorphone ER group

(16% vs. 4%, p=0.04). This result, however, may be confounded by a statistically significantly


58

higher proportion of patients treated with morphine ER who used other medications with a

risk for constipation (62% vs. 26%, p=0.0003). By contrast, the double-blind head-to-head

RCT(42) comparing morphine ER with hydromorphone ER in 163 patients during a duration

of 10-15 days revealed a lower incidence of patients reporting constipation in the morphine

ER group than in hydromorphone ER group (22.1% vs. 39.0%;p=NR).(42)

Because of methodological limitations, imprecision, and inconsistency of results, the

strength of evidence that morphine ER and hydromorphone ER have a similar risk for

constipation is very low (Appendix-Table 6).


The only evidence available for this comparison was a retrospective cohort study rated as

unclear risk of bias.(48) This study was based on Medicaid administrative claims data of 810

patients diagnosed with cancer that had at least one prescription of a 28 days or longer

supply of morphine ER or oxycodone ER. These dosages were comparable. Results showed a

similar risk of constipation for patients taking either drug (HR: 0.52, 95%: CI 0.19 to

1.39).(48)


study assessed this outcome, the strength of evidence that morphine ER and oxycodone ER

have a similar risk for constipation is very low (Appendix-Table 7).


Three studies, one retrospective cohort study (n=778)(48) with unclear risk of bias and two

non-blinded RCTs (n=203)(43, 44) rated as high risk of bias provided information on this

comparison. Overall, these studies reported similar rates of constipation for patients treated

with morphine ER or transdermal fentanyl ER.

The retrospective cohort study used Medicaid administrative claims data of 778 cancer

patients who had at least one prescription of a 28 days or longer supply of morphine ER or

transdermal fentanyl ER. Results indicated that patients treated with morphine ER and

transdermal fentanyl ER had a similar risk of constipation (HR 1.24, 95% CI: 0.51-2.99),

although the morphine-dose-equivalent for transdermal fentanyl was 20% higher in

comparison to the morphine treatment dosage.(48) Results of two non-blinded RCTs support


59

these findings although in one RCT(43) the morphine-dose equivalent for transdermal

fentanyl was 30% lower in comparison to the morphine treatment dosage.(43, 44)

Because of methodological limitations, and imprecision of results, the strength of evidence

that morphine ER and transdermal fentanyl ER have a similar risk for constipation is low

(Appendix-Table 8).

Oral Hydromorphone ER vs. Transdermal Fentanyl ER

The only evidence available for this comparison resulted from a prospective cohort study

(n=113) with unclear risk of bias designed to investigate adverse events.(46) This study

revealed that patients treated with hydromorphone ER and transdermal fentanyl ER had a

similar risk of constipation. An exception, however, the stool-free interval for more than 72

hours which was lower in patients on hydromorphone ER than transdermal fentanyl ER (2%

vs. 19%, p=NR). This result may be confounded by a shorter overall duration of opioid use of

hydromorphone ER-treated patients than patients on transdermal fentanyl ER (median use

60 days vs. 90 days).



transdermal fentanyl ER have a similar risk for constipation is very low (Appendix-Table 10).

Oral Hydromorphone ER vs. Transdermal Buprenorphine ER

One study (n=119) compared the risk of constipation of hydromorphone ER and transdermal

buprenorphine ER.(46) Patients treated with hydromorphone ER or transdermal

buprenorphine ER had a similar risk of constipation despite a 60% higher morphine-dose

equivalence of hydromorphone ER than transdermal buprenorphine. An exception,

however, was the stool-free interval for more than 72 hours which was substantially lower in

patients on hydromorphone ER than transdermal buprenorphine ER (2% vs. 21%, p=NR).

Confounding, however, is conceivable because patients on hydromorphone ER had a shorter

duration of opioid use than patients on transdermal buprenorphine ER (median use 60 days

vs. 90 days).

Because of methodological limitations, inconsistency of results, and imprecision of results,

and the fact that only a single study assessed this outcome, the strength of evidence that


60

hydromorphone ER and transdermal buprenorphine ER have a similar risk for constipation is

very low (Appendix-Table 11).


The only evidence available for this comparison was a high risk of bias RCT comparing the

self-reported symptoms of constipation in 184 patients treated with oral oxycodone ER and

oral oxycodone ER plus naloxone over a treatment period of four weeks.(41) Overall, the

study favoured oral oxycodone ER plus naloxone.

Constipation, as the primary outcome of this study, was measured by the Bowel Function

Index (51), the Patient Assessment of Constipation Symptoms and the European

Organisation of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC

QLQ-C30) constipation subscore. After four weeks, patients receiving oral oxycodone ER

experienced a smaller improvement in bowel function than patients receiving oral

oxycodone plus naloxone ER (difference between the groups in the change in the Bowel

Function Index score from baseline to endpoint: -11.14, 95% CI: -19.03 to -3.24).(41)

Furthermore, patients receiving oral oxycodone ER showed a smaller improvement in the

Patient Assessment of Constipation Symptoms in terms of total symptom score (score mean

changes from baseline to four weeks: oxycodone ER -2.74 vs. oxycodone ER plus naloxone -

7.01; p=0.014) and frequency of symptoms (mean 2.03 vs. 1.47; p<0.01) and a clinically

important smaller improvement in EORTC QLQ-C30 constipation subscore (mean change -

13.1 vs. - 30.4, p=NR).(41)

Because of methodological limitations, some inconsistent findings, imprecision of results and

the fact that only a single study assessed this outcome, the strength of evidence that

oxycodone ER has a higher risk of constipation than oxycodone ER plus naloxone is low

(Appendix-Table 12).

Transdermal Fentanyl ER vs. Transdermal Buprenorphine ER

We found one prospective controlled cohort study(46) with unclear risk of bias comparing

the effects of transdermal fentanyl ER with transdermal buprenorphine ER in 116 patients.

Overall, the study reported no statistically significant differences in constipation among

patients although morphine-dose-equivalent for transdermal fentanyl was 100% higher than

for transdermal buprenorphine.(46)


61


study assessed this outcome, the strength of evidence that transdermal fentanyl ER and

transdermal buprenorphine ER have a similar risk for constipation is very low (Appendix-

Table 14).


62

Table 23: Study Characteristics and Summary of Findings of Constipation.

Study N Duration Comparison and Dose Outcome Measure Constipation Risk of Bias




10-15 days Morphine ER: 60-540 mg/d Hydromorphone ER: 16-96 mg/d

Constipation reported by patients

Lower incidence of constipation for morphine ER: 22.1% vs. 39.0%; p=NR

High

Wirz et al., 2008(45)

100 Minimum 4 weeks treatment, 5 days observation of AE

Morphine ER: median (range) 60 (20-450) mg/d Hydromorphone ER (morphine equivalence 1:5): 80 (20-480) mg/d

Numerical rating scale for constipation (NRS, 0-10, 0=no symptom, 10=worst symptom imaginable)

Mean intensity of constipation was similar: 2.7% vs. 2.2%; p=0.35

Unclear

Four point EORTC QLQ 30 questionnaire, item on constipation (1=not at all, 2=a little, 3=quite a bit, 4=very much)

Mean scores for constipation were similar: 2.2% vs. 1.9%; p=0.18

Mean number of defecations of all patients per day

The mean defecation rate was similar: 1% vs. 0.9%; p=0.44

Stool free interval >72h More patients in the morphine ER group compared to the hydromorphone ER group had a stool free interval >72h: 16% vs., 4%; p=0.04



810 NR Morphine ER: mean±SD 85.1±60.0 mg/d Oxycodone ER: morphine equivalent dose: 75.47±58.7 mg/d

ED and hospitalization with an ICD-9 diagnosis code for constipation (564.0)

Similar risk for ED or hospital encounter for constipation: HR 0.52, 95% CI: 0.19-1.39

Unclear


63




778 NR Morphine ER: mean±SD 85.1±60.0 mg/d Transdermal Fentanyl ER: morphine equivalent dose 102.76±90.0 mg/d

ED and hospitalization with an ICD-9 diagnosis code for constipation (564.0)

Similar risk for ED or hospital encounter for constipation: HR 1.24, 95% CI: 0.51-2.99

Unclear


72 4 weeks Initial doses morphine ER: 60 mg/d

Transdermal Fentanyl ER: 25 µg/h

4-point scale for constipation (0=one passage/1-2 days, 1=one passage/3-4 days, 2=one passage >4 days, 3=rectal measures)

Similar risk of constipation between the groups: 0.8% vs. 0.4%; p=NR

High


131 4 weeks Morphine ER: average max. dose (range) 105 (30-400) mg/d Transdermal Fentanyl ER: average max. dose (range) 67 (25-400) µg/h

Questionnaire concerning predominant bowel function (normal, constipated or diarrhoeal) during the previous 7 days

Similar risk of constipation with constipation at endpoint: 37% vs. 30%; p=0.613

High

Reporting of constipation as adverse event

Similar number of patients reporting constipation: n=18, 28% vs. n=12, 18%; p=NS


Wirz et al., 2009 (46)


Hydromorphone ER (morphine equivalence 1:5) median (range): 80 (20-520) mg/d Transdermal Fentanyl ER (morphine equivalence 1:100): 120 (60-720) mg/d

Numerical rating scale for constipation (NRS, 0–10, 0 = no symptom, 10 = worst symptom imaginable)

Mean intensity of constipation was similar : 2.2% vs. 2.4%; p=NR

Unclear


64



Mean scores for constipation were similar : 1.9% vs. 2.1%; p=NR


The mean defecation rate was similar : 0.8% vs. 0.7%; p=NR

Stool free interval >72h Fewer patients in the hydromorphone ER group than in the transdermal fentanyl ER group had a stool free interval >72h n=1 vs. 12; p=NR


Wirz et al., 2009 (46)


Hydromorphone ER (morphine equivalence 1:5) median (range): 80 (20-520) mg/d Transdermal Buprenorphine ER (morphine equivalence 1:75): 90 (30-180) mg/d

Numerical rating scale for constipation (NRS, 0–10, 0 = no symptom, 10 = worst symptom imaginable)

Mean intensity of constipation was similar : 2.2% vs. 2.2%; p=NR

Unclear




The mean defecation rate was similar: 0.8% vs. 0.8%; p=NR

Stool free interval >72h Fewer patients in the hydromorphone ER than in the transdermal buprenorphine ER group had a stool free interval >72h: n=1 vs. 13, p=NR


65


Oral Oxycodone ER vs. Oxycodone plus Naloxone ER


184 4 weeks Oxycodone ER: mean 43.09 (SD 19.31) mg/d Oxycodone ER plus naloxone: 46.59 (SD 22.58) mg/d

Bowel function index (BFI) (0-100)

Less improvement in the oxycodone ER than oxycodone plus naloxone ER group: difference between groups -11.14%; p<0.01

High

PAC-SYM: Patient Assessment of Constipation Symptoms

Scores improved less in oxycodone ER than in oxycodone plus naloxone ER group: total symptom score mean change -2.74% vs. -7.01%; p=0.014

PAC-SYM: Patient Assessment of Constipation Symptoms

Frequency of symptoms decreased less in oxycodone ER than in oxycodone plus naloxone ER group: baseline mean 2.33% vs. 2.53%, at 4 weeks 2.03% vs. 1.47%; p<0.01

EORTC QLQ-C30 constipation subscore

Scores comparable at baseline, improvement after 4 weeks less in oxycodone ER than in oxycodone plus naloxone ER group: mean change from baseline -13.1% vs. -30.4%; p=NR


Wirz et al., 2009 (46)


Transdermal Fentanyl ER (morphine equivalence 1:100) median (range): 120 (60-720) mg/d Transdermal Buprenorphine ER (morphine equivalence 1:75): 90 (30-180) mg/d

Numerical rating scale (NRS, 0–10, 0 = no symptom, 10 = worst symptom imaginable)

Mean intensity of constipation was similar: 2.4% vs. 2.2%; p=NR

Unclear


66





The mean defecation rate was similar : 0.7% vs. 0.8%; p=NR

Stool free interval >72h Similar number of patients had a stool free interval >72h in both study groups: transdermal fentanyl ER: 12%, transdermal buprenorphine ER: 13%; p=NR

Abbreviations: AE, adverse events; BFI, bowel function index; CI, confidence interval; d, day; ED, emergency department; EORTC QLQ 30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30; ER, extended-release; h, hour; HR, hazard ratio; ICD, International Classification of Diseases; mg, milligram; n, number of participants; NR, not reported; NRS, numerical rating scale; NS, not significant; p, probability; PAC-SYM, Patient Assessment of Constipation Symptoms; SD, standard deviation; vs., versus; μg, microgram.


67

4.5.3.4 Nausea and Vomiting

Eight studies with more than 1500 patients provided data on the comparative risk of nausea

and vomiting of extended-release opioids.(40-47) Findings of these studies are presented in

Table 24.


Two studies, a prospective cohort study (n=100)(45), rated as unclear risk of bias and a high

risk of bias RCT (n=200, ER-phase: 163)(42) reported data on the comparative risk of nausea

and vomiting for morphine ER and hydromorphone ER. In the prospective study the number

of patients with at least one episode of vomiting during an observation period of five days

did not differ significantly between the study groups (morphine ER: 30%, hydromorphone

ER: 36%, p=0.52).(45) The mean number of vomits per day was higher in the morphine ER

group than in the hydromorphone ER group (0.7 vs. 0.1; p=0.0001).(45) For nausea-intensity

two different scales were used: The numerical rating scale (0-10) showed statistically

significant differences (2.5 points for morphine ER vs. 1.5 points for hydromorphone ER;

p=0.01). The EORTC-questionnaire evaluated nausea on a scale from 1-4 and showed no

statistically different results between the two treatment groups (1.6 for morphine ER and 1.8

for hydromorphone ER, p=0.23). The mean morphine equivalent dose of hydromorphone ER

was 45% to 100% higher than in the morphine ER-group.

The second study, a high risk of bias RCT reported adverse events, based on patient reports.

In the ER-phase, nausea was reported by 29.1% (25/86) of patients taking morphine ER

versus 19.5% (15/77) of patients taking hydromorphone ER. We calculated the OR of the

difference which was not statistically significant (OR 1.69, 95% CI: 0.82-3.52).(42) Vomiting

rates, however, were statistically significant higher for patients taking morphine ER with

22.1% (19/86) versus 9.1% (7/77) for hydromorphone ER (OR 2.84, 95% CI: 1.17-7.18).

Nausea-intensity scores and the number of patients with at least one episode of vomiting in

the prospective study showed similar results for morphine ER and hydromorphone ER. The

authors of the study used two different ratios to define the morphine-equivalence of

hydromorphone ER (1:5 and 1:7.5). Depending on the ratio the mean morphine equivalent

dose of hydromorphone ER was from 45% to 100% higher than morphine ER. No data for


68

morphine-equivalency could be calculated for the high risk of bias RCT. The RCT showed no

statistically significant difference of nausea between morphine and hydromorphone but a

higher risk of vomiting for patients takingmorphine.

Because of methodological limitations, imprecision of results, and inconsistent findings of

the included studies, the strength of evidence that oral morphine ER has a higher risk of

nausea and vomiting than hydromorphone is very low (see Appendix-Table 6).


We found only one high risk of bias retrospective cohort study, based on a registry of the

Osaka University, which compared morphine ER with oxycodone ER.(47) This study enrolled

413 cancer patients, with data available on 262 patients for the morpine ER versus

oxycodone ER comparison. Results indicated numerically lower rates of nausea for patients

treated within morphine ER than oxycodone ER (22.6% vs. 35.4%). The difference, however,

did not reach statistical significance (OR 0.53, 95% CI: 0.27-1.05). We were unable to assess

the dosing equivalence for this study.

Because of substantial methodological shortcomings, results from this study cannot be used

to draw any conclusion about differences in the risk of nausea and vomiting between

morphine ER and oxycodone ER. The strength of evidence that morphine ER has a lower risk

of nausea than oxycodone ER is very low (see Appendix-Table 7).


Three high risk of bias studies, two non-blinded RCTs(43, 44) and one retrospective cohort

study(47), based on 397 patients reported inconsistent results concerning the comparative

risk of nausea and vomiting between morphine ER and transdermal fentanyl ER. For example

in one of the RCT´s 41% of patients in the morphine ER group reported nausea, compared

with 37% in the transdermal fentanyl ER group (OR 1.15, 95% CI, 0.57-2.32). Likewise, rates

of vomiting were similar (31% vs. 28%; OR 1.15, 95% CI, 0.54-2.43).(44) The second RCT also

reported similar ratings for nausea and vomiting although the mean morphine-equivalent

dose of transdermal fentanyl ER was 30% lower than morphine ER.(28)By contrast, the

retrospective cohort study with data on 194 patients, however, reported a statistically


69

significantly higher risk of nausea for patients treated with morphine ER than transdermal

fentanyl ER (22.6% vs. 6.8%, OR 3.99, 95% CI 1.62-9.82).(47)

Because of methodological limitations, imprecision of results, and inconsistent findings of

included studies, the strength of evidence that oral morphine ER and transdermal fentanyl

ER have a similar risk for nausea and vomiting is very low (see Appendix-Table 8).


One double-blind RCT (n=44), rated as high risk of bias, showed similar mean nausea

intensity scores between hydromorphone ER and oxycodone ER (VAS: 16.05 vs. 16.68)

during a study period of seven days,(40) despite the fact that the the mean morphine-

eqivalent dose of oxycodone ER was 50% higher than that of hdromorphone ER.



oxycodone ER have a similar risk for nausea and is very low (see Appendix-Table 9).


Only one prospective cohort study of unclear risk of bias provided information on the

comparative risk of nausea and vomiting between hydromorphone ER and transdermal

fentanyl ER (n= 113).(46) Nausea was assessed using a numerical rating scale (NRS) from no

nausea (0), to worst imaginable nausea(10), and the four point EORTC QLQ 30 questionnaire.

Overall, results indicated similar nausea intensity-scores and vomiting scores (EORTC) in

patients treated with hydromorphone ER or transdermal fentanyl ER. The NRS – scale (0-10)

for nausea showed 1.5 points for hydromorphone ER and 1.3 points for transdermal fentanyl

ER. Patients on hydromorphone ER, however, reported statistically significantly higher rates

of vomiting than patients on transdermal fentanyl ER (33% vs. 16%; OR 2.49, 95% CI: 1.01-

6.13) during a 5-day follow-up period. The authors of the study used two different ratios to

define the morphine-equivalent dose of hydromorphone (1:5 and 1:7.5). Consequently, the

morphine-equivalent dose of hydromorphone ER varied from 20 % lower (for the 1:5 ratio)

to 20% higher (for the 1:7.5 ratio) compared with the morphine-equivalent dose of

transdermal fentanyl ER.


70


study assessed this outcome, the strength of evidence that hydromorphone ER transdermal

fentanyl ER have a similar risk for nausea is very low. In addition the strength of evidence,

that hydromorphone ER has a higher risk for vomiting than transdermal fentanyl ER is also

very low (see Appendix-Table 10).


The same prospective cohort study described in the previous section(46) showed similar

nausea and vomiting scores (NRS) for patients receiving hydromorphone ER (n=58) and

transdermal buprenorphine ER (n=61As mentioned above, authors defined two different

ratios of morphine-equivalence for hydromorphone ER (1:5 and 1:7.5). Consequently, the

mean morphine-equivalent dose of hydromorphone ER was from 60 % (for the 1:5 ratio) to

140% (for the 1:7.5 ratio) higher than the morphine equivalent dose of transdermal

buprenorphine ER.


study assessed this outcome, the strength of evidence that hydromorphone ER and have a

similar risk for nausea and higher risk for vomiting than transdermal buprenorphine ER is

very low.(see Appendix-Table 11)


A high risk of bias double-blind RCT (n=184) with a duration of four weeks showed that

nausea was more frequent in patients receiving oxycodone ER (13%) compared to those on

oxycodone plus naloxone ER (7.6%), but the difference was not statistically significant (OR

1.82, 95% CI: 0.68-4.86).(41) Vomiting rates were similar among the study groups and

showed no statistically significant difference (oxycodone ER 5.4% and oxycodone plus

naloxone ER 6.5%; OR 0.82, 95% CI: 0.24-2.80).



plus naloxone ER have a similar risk for nausea and vomiting is very low (see Appendix-Table

12).


71

Oral Oxycodone ER vs. Transdermal Fentanyl ER

One high risk of bias retrospective study with data of 296 patients showed that nausea

occurred more frequently in the oxycodone ER group (35.4%) than in the transdermal

fentanyl ER group (6.8%), OR 7.48, 95% CI: 3.54-15.81, based on internal calculations).(47)


study assessed this outcome, the strength of evidence that oxycodone ER has a higher risk of

nausea than transdermal fentanyl ER is very low (see Appendix-Table 13).


The prospective cohort study with an unclear risk of bias, by Wirz et al. investigated 116

patients who received transdermal fentanyl ER or transdermal buprenorphine ER for at least

28 days prior to the five day data collection period.(46) Results showed similar low mean

nausea intensity-scores on a 0-10-scale with 1.3 points for transdermal fentanyl ER and 1.2

points for transdermal buprenorphine ER. The study reported also similar absolute numbers

of vomiting patients (transdermal fentanyl ER: 16% vs. transdermal buprenorphine ER: 13%,

OR 1.3, 95% CI: 0.46-3.63), although the mean morphine-eqivalent dose of transdermal

fentanyl ER was 100 % higher than that of transdermal buprenorphine ER-group.(46)


study assessed this outcome, the strength of evidence that transdermal fentanyl ER and

transdermal buprenorphine ER have a similar risk for nausea and vomiting is very low. (see

Appendix-Table 14)


72

Table 24: Study Characteristics and Summary of Findings o Nausea and Vomiting.

Study N Duration Comparison and Dose Outcome Measure Nausea and Vomiting Risk of Bias



200 ER-phase: 163


Nausea reported by patients

Higher incidence of nausea with ER morphine ER vs. hydromorphone ER (n=25, 29.1% vs. n=15, 19.5%; p=NR, *OR 1.69, 95% CI: 0.82-3.52)

High

Vomiting reported by patients

Higher incidence of vomiting with morphine ER vs. hydromorphone ER (n=19, 22.1% vs. n=7, 9.1%; p=NR, *OR 2.84, 95% CI: 1.17-7.18)

Wirz et al., 2008(45)


Morphine ER: median (range) 60 (20-450) mg/d Hydromorphone ER (morphine equivalence 1:5): 80 (20-480) mg/d

Numerical rating scale (NRS, 0-10, 0=no symptom, 10=worst symptom imaginable)

Mean intensity of nausea scores were higher in the morphine ER group compared to the hydromorphone ER group (2.5 vs. 1.5; p=0.01)

Unclear

Four point EORTC QLQ 30 questionnaire, item on nausea (1=not at all, 2=a little, 3=quite a bit, 4=very much)

Mean nausea scores were similar for both study groups (morphine ER: 1.6, hydromorphone ER: 1.8; p=0.23)

Four point EORTC QLQ 30 questionnaire, item on vomiting (1=not at all, 2=a little, 3=quite a bit, 4=very much)

Mean vomiting scores were similar for both study groups (morphine ER: 1.5, hydromorphone ER: 1.4; p=0.53)

Number of patients with at least 1 vomit during observation period

Similar number of patients with vomiting (morphine ER: n=15, 30%, hydromorphone ER: n=18, 36%; p=0.52)

Numbers of vomits/day Mean number of vomits per day was higher in the morphine ER group than in the hydromorphone ER group (0.7 vs. 0.1; p=0.0001)


73




262 NR Morphine ER: NR Oxycodone ER NR

Nausea during daytime that developed within 2 days after commencement of opioid; outcome measure NR

Lower incidence of nausea in the ER morphine ER than in the oxycodone ER group (22.6% vs. 35.4%; p=NS, *OR 0.53, 95% CI 0.27-1.05)

Unclear



72 4 weeks Initial doses morphine ER: 60 mg/d

Transdermal fentanyl ER: 25 µg/h

4-point scale for nausea/vomiting (0=not at all, 1=slight, 2=a lot, 3=severe)

Similar rating for nausea/vomiting at endpoint ( morphine ER 0.6, transdermal fentanyl ER 0.6; p=NR)

High


194 NR Morphine ER: NR Transdermal fentanyl ER: NR


Higher incidence of nausea in the morphine ER than the transdermal fentanyl ER group (22.6% [14/62] vs. 6.8% [9/132];*OR 3.99, 95% CI: 1.62-9.82)

High


131 4 weeks Morphine ER: average max. dose (range) 105 (30-400) mg/d Transdermal fentanyl ER: average max. dose (range) 67 (25-400) µg/h

4-point scale for nausea (1=not at all, 4=very much)

No difference for nausea at baseline; change from baseline to week 4 was similar among groups ( morphine ER: 0.2 vs. transdermal fentanyl ER: 0.2; p=0.755)

High


Similar numbers of patients reporting nausea in the ER morphine ER and in the transdermal fentanyl ER group (n=26, 41% vs. n=25, 37%; p=NS,* OR 1.15, 95% CI, 0.57-2.32)

4-point scale for vomiting (1=not at all, 4=very much)

No difference for vomiting at baseline; change from baseline to week 4 was similar among groups (morphine ER: -0.1 vs. transdermal fentanyl ER: 0.2; p=0.390)


74



Similar numbers of patients reporting vomiting in the morphine ER and in the transdermal fentanyl ER group (n=20, 31% vs. n=19, 28%; p=NS, *OR 1.15, 95% CI: 0.54-2.43)



44 7 days Hydromorphone ER: mean final dose 30 ± 6 mg/d oxycodone ER: 124 ± 22 mg/d

VAS 0-100mm for nausea (0=no nausea, 100=severe nausea)

Overall mean nausea scores similar for both groups (hydromorphone ER: 16.05 vs. oxycodone ER: 16.68; p=NR)

High


Wirz et al., 2009 (46)


Hydromorphone ER (morphine equivalence 1:5) median (range): 80 (20-520) mg/d Transdermal fentanyl ER (morphine equivalence 1:100): 120 (60-720) mg/d

Numerical rating scale for nausea (NRS, 0-10, 0=no symptom, 10=worst symptom imaginable)

Mean intensity of nausea scores were similar for both study groups (hydromorphone ER: 1.5, transdermal fentanyl ER: 1.3; p=NR)

Unclear


Mean nausea scores were similar for both study groups ( hydromorphone ER: 1.8, transdermal fentanyl ER: 1.8; p=NR)


Mean vomiting scores were similar for both study groups ( hydromorphone ER: 1.4, transdermal fentanyl ER: 1.6; p=NR)


Higher number of patients with vomiting (hydromorphone ER: n=19, 33%, transdermal fentanyl ER: n=9, 16%; p=NR, * OR 2.49, 95% CI: 1.01-6.13)


75


Numbers of vomits/day Mean number of vomits per day were similar for both study groups (hydromorphone ER: 0.1, transdermal fentanyl ER: 0.1; p=NR)

Oral Hdromorphone ER vs. Transdermal Buprenorphine ER

Wirz et al., 2009 (46)


Hydromorphone ER (morphine equivalence 1:5) median (range): 80 (20-520) mg/d Transdermal buprenorphine ER (morphine equivalence 1:75): 90 (30-180) mg/d


Mean intensity of nausea scores were similar for both study groups (hydromorphone ER: 1.5, transdermal buprenorphine ER: 1.2; p=NR)

Unclear


Mean nausea scores were similar for both study groups (hydromorphone ER: 1.8, transdermal buprenorphine ER: 1.7; p=NR)


Mean vomiting scores were similar for both study groups (hydromorphone ER: 1.4, transdermal buprenorphine ER: 1.4; p=NR)


Higher number of patients with vomiting (hydromorphone ER: n=19, 33%, transdermal buprenorphine ER: n=8, 13%; p=NR, *OR 3.23, 95% CI: 1.28-8.13)

Numbers of vomits/day Mean number of vomits per day were similar for both study groups (hydromorphone ER: 0.1, transdermal buprenorphine ER: 0.1; p=NR)


76






Higher incidence of nausea in oxycodone ER group compared to oxycodone plus naloxone ER (n=12, 13% vs. n=7, 7.6%; p=NR, *OR 1.82, 95% CI: 0.68-4.86)

High


Similar incidence of vomiting among both groups ( oxycodone ER: n=5, 5.4% vs. oxycodone plus naloxone ER: n=6, 6.5%; p=NR, *OR 0.82, 95% CI 0.24-2.80)



296 NR Oxycodone ER: NR Transdermal fentanyl ER: NR


Higher incidence of nausea in the oxycodone ER than the transdermal fentanyl ER group (35.4% [58/164] vs. 6.8% [9/132]; *OR 7.48, 95% CI: 3.54-15.81, p<0.001)

High


Wirz et al., 2009 (46)


Transdermal Fentanyl ER (morphine equivalence 1:100) median (range): 120 (60-720) mg/d Transdermal buprenorphine ER (morphine equivalence 1:75): 90 (30-180) mg/d


Mean intensity of nausea scores were similar for both study groups (transdermal fentanyl ER: 1.3, transdermal buprenorphine ER: 1.2; p=NR)

Unclear


Mean nausea scores were similar for both study groups (transdermal fentanyl ER: 1.8, transdermal buprenorphine ER: 1.7; p=NR)


Mean vomiting scores were similar for both study groups (Transdermal fentanyl ER: 1.6, buprenorphine ER: 1.4; p=NR)


77



Similar number of patients with vomiting (Transdermal fentanyl ER: n=9, 16%, buprenorphine ER: n=8,

13%; p=NR) *OR 1.3, 95% CI: 0.46-

3.63

Numbers of vomits/day Mean number of vomits per day were similar for both study groups (Transdermal fentanyl ER: 0.1, buprenorphine ER: 0.1; p=NR)

*based on internal calculations

Abbreviations: AE, adverse events; CI, confidence interval; d, day; ER, extended-release; EORTC QLQ 30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30; h, hour; mg, milligram; n, number of participants; NR, not reported; NRS, numerical rating scale; NS, not significant; OR, odds ratio; p, probability; SD, standard deviation; VAS, visual analogue scale; vs., versus; μg, microgram.


78

4.5.3.5 Dizziness

The reporting of information regarding the risk of dizziness was generally inadequate.

Among the nine studies analyzed in this report, only one double-blind RCT(42) reported on

the comparative risk of dizziness associated with the use of long-acting opioids. We rated

this study as having a high risk of bias. The study’s findings are summarized in Table 25.


The only available evidence for this comparison was a multicenter, double-blind, head-to-

head RCT with a high risk of bias, which was funded by the ALZA Corporation, the producer

of hydromorphone.(42) Two hundred patients were initially randomized to immediate-

release morphine (n=101) or immediate-release hydromorphone (n=99). Eighty-six patients

completed the morphine IR phase and were then switched to morphine ER. Seventy-seven

patients completed the hydromorphone IR phase and then began taking hydromorphone ER.

During the ER phase, the study reported that morphine ER led to numerically more instances

of dizziness than hydromorphone ER (9.3% and 5.2% respectively). Event rates, however,

were small and thus results must be interpreted cautiously.

Table 25: Studies Assessing Dizziness.


Outcome Measure

Dizziness Risk of Bias





Dizziness reported by patients

Similar rates of dizziness: 5.2% vs. 9.3%; p=NR

High

Abbreviations: d, day; ER, extended-release; IR, immediate-release; mg, milligram; N, number of participants; NR, not reported; p, probability; vs., versus; μg, microgram.

4.5.3.6 Drowsiness, Somnolence, Fatigue, Sedation

The reporting of adverse events for drowsiness, somnolence, fatigue, and sedation was

limited. Among the nine studies analyzed in this report, four reported on the incidence of

drowsiness, somnolence, fatigue, and sedation associated with the use of extended-release

opioids.(42-44, 47) Table 26 summarizes findings of included studies.


79


The only available evidence for this comparison was a two-phase (IR phase and ER phase)

RCT on the equivalence of morphine ER and hydromorphone ER.(42) In this high risk of bias

study, patients (n=200 IR phase; n=163 ER phase) treated with morphine ER had a similar

reported incidence of somnolence (14.0%) and fatigue (7.0%) compared with those taking

hydromorphone ER (10.4% and 5.2%, respectively). Since the article only reported dosing

ranges we were unable to assess dosing equivalence. Overall, insufficient evidence is

available to draw firm conclusions about the comparative risk of somnolence and fatigue,

between morphine ER and hydromorphone ER.


One high risk of bias study comparing morphine ER and oxycodone ER met our inclusion

criteria.(47) This retrospective chart review was conducted in Japan between October 2004

and April 2007. The study found that patients (n=66) treated with morphine ER had a similar

risk of opioid-induced somnolence (i.e., somnolence that developed within two days after

commencement of opioid without any other reason) compared with patients (n=196)

treated with oxycodone ER (31.3% vs. 39.9%, p=NS). Mean administered dosages of

morphine ER and oxycodone ER were not reported. Therefore, we could not determine if the

doses administered of morphine ER and oxycodone ER were equivalent.


Three studies, one with unclear risk of bias and two with high risk of bias, reported on

somnolence and drowsiness for this comparison.(43, 44, 47) In a retrospective cohort study

with unclear risk of bias, a chart review of 413 patients found that treatment with morphine

ER (n=66) led to a higher incidence of opioid-induced somnolence than treatment with

transdermal fentanyl ER (n=151) (31.3% vs. 9.8%, p<0.001); dosage equivalence was

indeterminate.(47) Converseley, an open-label RCT (n=131) with high risk of bias, comparing

the safety of oral morphine ER versus transdermal fentanyl ER, found a similar risk for

drowsiness between the two groups (37.5% vs. 35.8%, respectively). The

morphineequivalent dose of fentanyl ER was 20% higher than the morphine ER dose This

trial was conducted over 28 days at 26 Dutch investigational sites between June 1998 and

June 2000.(44)


80

An open-label RCT (n=72) also compared morphine ER versus transdermal fentanyl ER.

However, due to the high risk of bias and low quality of evidence (for adverse events only,

within group comparisons were presented), no inferences can be made from this study

about differences between the two drugs in opioid-induced drowsiness in cancer

patients.(43)


One study met our eligibility criteria for this comparison - a high risk of bias RCT (n=44)

comparing the safety of hydromorphone ER versus oxycodone ER over a study period of

seven days.(40)

There were no significant differences between treatments in sedation VAS when tested by

time of day (p=0.11) and by day of treatment (p=0.1114). Patients who received

hydromorphone ER, however, had fewer overall reported incidents of sedation than patients

who took oxycodone ER (19.92% vs. 24.81%; p=NR). Results should be interepreted with

caution because the mean morphine-dose-equivalent of oxycodone ER (124 mg/d) was 50%

higher than that of hydromorphone ER (30 mg/d).


The only available evidence for this comparison was a high risk of bias retrospective chart

review that collected data on somnolence from the Japanese medical records of patients

suffering from cancer pain. Patients (n=196) treated with oxycodone ER had a higher

incidence of opioid-induced somnolence than patients (n=151) treated with transdermal

fentanyl ER (39.9% vs. 9.8%, p<0.001).(47) Dosgae equivallencies could not be determined

because mean adminstered dosages were not reported (only ranges).


81

Table 26: Studies Assessing Drowsiness, Somnolence, Fatigue, or Sedation.

Study N Duration Comparison and Dose Outcome Measure Drowsiness, Somnolence or Fatigue

Risk of Bias

Oral Morphine ER vs. oral Hydromorphone ER



10-15 days Morphine ER: 60-540 mg/dHydromorphone ER: 16-96 mg/d

Somnolence reported by patients

Similar incidence of somnolence: 14.0% vs. 10.4%; p=NR

High

Fatigue reported by patients

Similar numbers of patients reporting fatigue: 7.0% vs. 5.2%; p=NR

Oral Morphine ER vs. oral Oxycodone ER


262 NR Morphine ER: 48.0±34.7 mg/d Oxycodone ER (oral morphine equivalent): 21.4±12.1 mg/d

Somnolence during daytime that developed within 2 days after commencement of opioid; outcome measure NR

Similar incidence of somnolence: 31.3% vs. 39.9%; p=NS

High



72 4 weeks Morphine ER: 60 mg/d Transdermal Fentanyl ER: 25 µg/h

4-point scale for drowsiness (0=not at all, 1=slight, 2=a lot, 3=severe)

Similar ratings for drowsiness: 0.6% vs. 0.9%; p=NR

High


217 NR Morphine ER: 48.0±34.7 mg/d Transdermal Fentanyl ER (oral morphine equivalent): 92.5±65.7 mg/d


Higher incidence of somnolence for patients treated with Morphine ER: 31.3% vs. 9.8%; p<0.001

High


131 4 weeks Morphine ER: average max. dose (range) 105 (30-400) mg/d Transdermal Fentanyl ER: 67 (25-400) µg/h

4-point scale for daytime drowsiness (1=not at all, 4=very much)

No difference for daytime drowsiness: 0.5% vs. 0.4%; p=0.973

High


82

Study N Duration Comparison and Dose Outcome Measure Drowsiness, Somnolence or Fatigue

Risk of Bias

Drowsiness reported by patients

Similar numbers of patients reporting drowsiness: n=24, 37.5% vs. n=24, 35.8%; p=NS

Epworth Sleepiness Scale: 4-point scale for 8 items (0=would never doze, 3=high chance of dozing)

No difference for daytime sleepiness: 4.8% vs. 2.9%; p=0.175



44 7 days Hydromorphone ER: mean final dose 30 ± 6 mg/d Oxycodone ER: 124 ± 22 mg/d

VAS 0-100mm for sedation (0=no sedation, 100=extreme sedation), assessed 4 times a day

Lower overall mean sedation score for patients treated with Hydromorphone ER: 19.92% vs. 24.81%; p=NR

High



347 NR Oxycodone ER (oral morphine equivalent): 21.4±12.1 mg/d Transdermal Fentanyl ER (oral morphine equivalent): 92.5±65.7 mg/d


Higher incidence of somnolence for patients treated with Oxycodone ER: 39.9% vs. 9.8%; p<0.001

High

Abbreviations: d, day; ER, extended-release; h, hour; IR, immediate-release; mg, milligram; n, number of participants; NR, not reported; NS, not significant; p, probability; VAS, visual analog scale; vs., versus; μg, microgram.


83

4.5.3.7 Diarrhea

Diarrhea has been reported as an adverse event of naloxone, an opioid antagonist. Only one

study addressed the risk of diarrhea.(41) Table 27 summarizes findings of the included study.


A high risk of bias RCT compared the reported symptoms of diarrhea in 184 patients treated

with oral oxycodone ER or oral oxycodone plus naloxone ER over a treatment period of four

weeks and showed no difference between the groups (4.3% vs. 4.3%).(41) We were unable

to assess the dosing equivalence of the administered drugs in this study because mean

dosages were not reported.

Table 27: Studies Assessing Diarrhea.


Outcome Measure

Diarrhea Risk of Bias



184 4 weeks Oxycodone ER: mean 43.09 (SD 19.31) mg/d oxycodone plus naloxone ER: 46.59 (SD 22.58) mg/d

Diarrhea reported by patients

Same number of patients reported diarrhea (n=4, 4.3% in both study groups; p=NR)

High

Abbreviations: d, day; ER, extended-release; mg, milligram; n, number of participants; NR, not reported; SD, standard deviation; vs., versus.

4.6 Key Question 3: Efficacy, Effectiveness, or Risk for Harms

in Subpopulations

We did not identify any study that addressed this key question.


84

5 Discussion

5.1 Key Findings and Strength of Evidence

This systematic review assesses the comparative efficacy, effectiveness and risk of harms of

extended-release opioids for the treatment of cancer-related pain. Overall, for most

interventions and outcomes of interest, evidence was either lacking or insufficient to draw

conclusions. Furthermore, in the evidence available, the eligible studies were fraught with

serious methodological shortcomings. Consequently, most of the conclusions have a very

high degree of uncertainty:

The comparative efficacy for improvement of pain intensity, quality of life, functional

capacity, and cognitive functioning was similar among compared drugs.

Discontinuation rates because of lack of efficacy were also similar. The strength of

evidence supporting similar efficacy among compared drugs is very low.

We could not find eligible evidence on the comparative efficacy of transdermal

buprenorphine ER, dihydrocodeine ER, transdermal fentanyl ER, morphine plus

naltrexone ER, nalbuphine ER, oxymorphone ER, tapentadol hydrochloride ER, and

tramadol ER.

With few exceptions, the comparative risk of harms was also similar among reviewed

drugs. Discontinuation rates because of adverse events were similar. The strength of

evidence supporting a similar risk of harms with respect to serious adverse events,

constipation, nausea and vomiting, dizziness, and somnolence among compared

drugs is low or very low.

A notable exception, albeit based on weak evidence, is that oxycodone ER had higher

risks of some adverse events than comparator drugs:

o a higher risk of drowsiness than hydromorphone ER;

o a higher risk of constipation than oxycodone plus naloxone ER;

o a higher risk of nausea than morphine ER and transdermal fentanyl ER;

o and a higher risk of somnolence than transdermal fentanyl ER.


85

GRADE Evidence Profiles with strength of evidence ratings for all outcomes within each

comparison can be found in Appendix E (Appendix-Table 3 to Appendix-Table 14).

5.2 Gaps in the Evidence

Three main drawbacks posed challenges for this review and limit findings about the

comparative efficacy and risk of harms of extended-release opioids. First, no studies existed

for many interventions. Out of 66 possible comparisons for this drug class, we found no

evidence on 75 comparisons for comparative efficacy, and 69 for comparative risk of harms.

Consequently, we can neither confirm nor rule out differences in the comparative efficacy

and risk of harms for the majority of comparisons. Second, the available evidence was often

limited to a single study with methodological shortcomings. Many of these studies did not

publish details about some attributes of their subjects (e.g., race or ethnicity); and generally

investigators did not report whether interventions were efficacious for subgroups.

Therefore, whether findings can be applied to subgroups with respect to sex, ethnicity, age,

moderate vs. severe cancer pain, breakthrough pain, or pain with a neuropathic component

is unclear. Furthermore, no evidence on patients taking other commonly prescribed co-

analgesics (e.g., non-steroidal anti-inflammatory drugs, antiepileptic drugs, antidepressants)

was available. Third, the few interventions with somewhat reliable evidence for the risk of

harms often had wide confidence intervals which lead to inconclusive results.


86

6 Conclusions

The evidence available indicates no substantial differences in efficacy and risk of harms

amongst extended-release opioids. The body of evidence, however, is limited to few

comparisons and fraught with methodological shortcomings. Generally, our confidence in

the available estimates is very low. We anticipate that future studies will change these

estimates. Given the lack of reliable evidence regarding the comparative benefits and harms

of extended-release opioids, clinicians should weigh clinical experience, patient preferences,

and treatment costs when choosing the optimal treatment for an individual cancer patient.


87

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90

8 Appendices

Appendix A

Search Strategy

Searches conducted on December 19, 2011

PubMed

#1

Search “Analgesics, Opioid"[Mesh] OR "Analgesics, Opioid" [Pharmacological Action]

OR "Buprenorphine"[Mesh] OR "Codeine"[Mesh] OR "Dextropropoxyphene"[Mesh]

OR "Fentanyl"[Mesh] OR "Hydromorphone"[Mesh] OR "Methadone"[Mesh] OR

"Morphine"[Mesh] OR "Morphine"[Substance Name] OR "Naloxone"[Mesh] OR

"Pirinitramide"[Mesh] OR "Tramadol"[Mesh] OR polamidon OR polamidone OR targin 98166

#2

Search ("Neoplasms"[Mesh] OR cancer[TIAB] OR tumor[TIAB] OR tumour[TIAB]) AND

("Pain"[Mesh] OR pain[TIAB]) 63265

#3

Search "Randomized Controlled Trial"[Publication Type] OR "Single-Blind

Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH]

OR "Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR "Epidemiologic

Studies"[MeSH] OR "Cross-Sectional Studies"[MeSH] OR "Cross-Over Studies"[MeSH]

OR "Follow-Up Studies"[MeSH] OR "Multicenter Study "[Publication Type] OR

"Evaluation Studies "[Publication Type] OR "Longitudinal Studies"[MeSH] OR

"Prospective Studies"[MeSH] OR "Validation Studies"[Publication Type] OR

observational studies OR evaluation studies [pt] OR systematic [sb] OR

(MEDLINE[Title/Abstract] OR systematic[Title/Abstract] AND review[Title/Abstract]

OR meta-analysis[Publication Type]) 2018360

#4 Search #1 AND #2 AND #3 1143

#5 Search #1 AND #2 AND #3 Limits: All Adult: 19+ years 895

Cochrane Library

#1 MeSH descriptor Analgesics, Opioid explode all trees 10908

#2 MeSH descriptor Buprenorphine explode all trees 551

#3 MeSH descriptor Codeine explode all trees 878

#4 MeSH descriptor Dextropropoxyphene explode all trees 177

#5 MeSH descriptor Fentanyl explode all trees 3657

#6 MeSH descriptor Hydromorphone explode all trees 151

#7 MeSH descriptor Methadone explode all trees 805

#8 MeSH descriptor Morphine explode all trees 4342

#9 MeSH descriptor Naloxone explode all trees 1386

#10 MeSH descriptor Pirinitramide explode all trees 86

http://www.ncbi.nlm.nih.gov/pubmed/?cmd=HistorySearch&querykey=47

http://www.ncbi.nlm.nih.gov/pubmed/advanced








http://onlinelibrary.wiley.com/o/cochrane/searchHistory?mode=runquery&qnum=1











91

#11 MeSH descriptor Tramadol explode all trees 595

#12 polamidon OR polamidone OR targin 2

#13 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12) 11919

#14 MeSH descriptor Neoplasms explode all trees 42033

#15 (cancer OR tumor OR tumour):ti,ab,kw 54099

#16 MeSH descriptor Pain explode all trees 28335

#17 (pain):ti,ab,kw 53226

#18 (#13 AND ( #14 OR #15) AND ( #16 OR #17)) 531

EMBASE

#1 'buprenorphine'/exp 9,560

#2 'codeine'/exp 15,746

#3 'dextropropoxyphene'/exp 6,643

#4 'fentanyl'/exp 40,208

#5 'hydromorphone'/exp 5,148

#6 'methadone'/exp 22,315

#7 'morphine'/exp 77,297

#8 'naloxone'/exp 35,212

#9 'pirinitramide'/exp 1,342

#10 'tramadol'/exp 10,157

#11 polamidone 25

#12 targin 27

#13 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 162,023

#14 'neoplasms'/exp 2,949,835

#15 'pain'/exp 652,107

#16 #13 AND #14 AND #15 5,223









92

#17 #16 AND ([cochrane review]/lim OR [controlled clinical trial]/lim OR [meta

analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim)

508

#18 #17 AND ([adult]/lim OR [aged]/lim) 348

IPA

S1 buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR

hydromorphone OR methadone OR morphine OR naloxone OR pirinitramide OR

tramadol OR polamidon OR polamidone OR targin

S2 TI ( neoplasm OR cancer OR tumor OR tumour ) OR AB ( neoplasm OR cancer OR

tumor OR tumour )

25806

S3 TI pain OR AB pain 12527

S4 S1 and S2 and S3 445

CINAHL

S1 buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR


tramadol OR polamidon OR polamidone OR targin


tumor OR tumour )

104806



BIOSIS

# 1 Topic=(buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR


tramadol OR polamidon OR polamidone OR targin) OR Title=(buprenorphine OR

codeine OR dextropropoxyphene OR fentanyl OR hydromorphone OR methadone OR

morphine OR naloxone OR pirinitramide OR tramadol OR polamidon OR polamidone

88,349

http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=2&SID=3Fo@L@hCPgNM3h75NKM&search_mode=GeneralSearch


93

OR targin)

Databases=BIOSIS Previews Timespan=All Years

# 2 Title=(neoplasm OR cancer OR tumor OR tumour)


716,532

# 3 Title=(pain)


58,887

# 4 #1 AND #2 AND #3


917



http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=9&SID=3Fo@L@hCPgNM3h75NKM&search_mode=CombineSearches


94

Searches conducted on February 1, 2012

PubMed

#1 Search "Heroin"[Mesh] OR "dihydrocodeine" [Supplementary Concept] OR "Nalbuphine"[Mesh] OR "Oxymorphone"[Mesh] OR "3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol" [Supplementary Concept]

5709

#2 Search "tapentadol hydrochloride" OR diamorphine OR dihydrocodeine 14588

#3 Search #1 OR #2 15565

#4 Search ("Neoplasms"[Mesh] OR cancer[TIAB] OR tumor[TIAB] OR tumour[TIAB]) AND ("Pain"[Mesh] OR pain[TIAB])

63783

#5 Search "Randomized Controlled Trial"[Publication Type] OR "Single-Blind Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH] OR "Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR "Epidemiologic Studies"[MeSH] OR "Cross-Sectional Studies"[MeSH] OR "Cross-Over Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR "Multicenter Study "[Publication Type] OR "Evaluation Studies "[Publication Type] OR "Longitudinal Studies"[MeSH] OR "Prospective Studies"[MeSH] OR "Validation Studies"[Publication Type] OR observational studies OR evaluation studies [pt] OR systematic [sb] OR (MEDLINE[Title/Abstract] OR systematic[Title/Abstract] AND review[Title/Abstract] OR meta-analysis[Publication Type])

2037975

#6 Search #3 AND #4 AND #5 37

#7 Search #3 AND #4 AND #5 Limits: All Adult: 19+ years 21

Cochrane Library

#1 MeSH descriptor Heroin explode all trees 233

#2 MeSH descriptor Nalbuphine explode all trees 177

#3 MeSH descriptor Oxymorphone explode all trees 42

#4 Diamorphine OR Dihydrocodeine OR "Tapentadol hydrochloride" 386

#5 (#1 OR #2 OR #3 OR #4) 735





#10 (#5 AND ( #6 OR #7 ) AND ( #8 AND #9 )) 21


























95

EMBASE

#1 'diamorphine'/exp OR 'dihydrocodeine'/exp OR 'oxymorphone'/exp OR

'tapentadol'/exp OR 'nalbuphine'/exp

22,348

#2 'neoplasm'/exp 2,974,9

16

#3 'pain'/exp 659,81

5

#4 #1 AND #2 AND #3

434

#5 #4 AND ([cochrane review]/lim OR [controlled clinical trial]/lim OR [meta

analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim)

23

CINAHL


tumor OR tumour )

105935


S3

Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride

OR Nalbuphine 241

S4 (Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride

OR Nalbuphine) and (S1 and S2 and S3)

17

BIOSIS

#1 Topic=(Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride OR Nalbuphine) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

1,822

# 2 Title=(neoplasm OR cancer OR tumor OR tumour) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

719,688

http://www.embase.com/search/results?viewsearch=1







http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=1&SID=3AOcM@c5MghIG@IhP89&search_mode=GeneralSearch



96

# 3 Title=(pain) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

59,486

# 4 #3 AND #2 AND #1 Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

24

IPA

S1 Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride

OR Nalbuphine

(333)


tumor OR tumour )

(25976)

S3 TI pain OR AB pain (12594)

S4 (TI pain OR AB pain) and (S1 and S2 and S3) (22)


http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=4&SID=3AOcM@c5MghIG@IhP89&search_mode=CombineSearches


97

Opioid Update Search -- 23 July 2012

PubMed

#1 Search “Analgesics, Opioid"[Mesh] OR "Analgesics, Opioid" [Pharmacological Action] OR "Buprenorphine"[Mesh] OR "Codeine"[Mesh] OR "Dextropropoxyphene"[Mesh] OR "Fentanyl"[Mesh] OR "Hydromorphone"[Mesh] OR "Methadone"[Mesh] OR "Morphine"[Mesh] OR "Morphine"[Substance Name] OR "Naloxone"[Mesh] OR "Pirinitramide"[Mesh] OR "Tramadol"[Mesh] OR polamidon OR polamidone OR targin

100031

#2 Search "Heroin"[Mesh] OR "dihydrocodeine" [Supplementary Concept] OR "Nalbuphine"[Mesh] OR "Oxymorphone"[Mesh] OR "3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol" [Supplementary Concept]

5774

#3 Search "tapentadol hydrochloride" OR diamorphine OR dihydrocodeine 14825

#4 Search #1 OR #2 OR #3 106270

#5 Search ("Neoplasms"[Mesh] OR cancer[tiab] OR tumor[tiab] OR tumour[tiab]) AND ("Pain"[Mesh] OR pain[tiab])

65832

#6 Search #4 AND #5 4290

#7 Search (("2011/12/01"[Date - Entrez] : "3000"[Date - Entrez])) AND #6 45

EMBASE

#1 'buprenorphine'/exp 9,985

#2 'codeine'/exp 16,166

#3 'dextropropoxyphene'/exp 6,739

#4 'fentanyl'/exp 41,815

#5 'hydromorphone'/exp 5,451

#6 'methadone'/exp 23,032

#7 'morphine'/exp 79,488

#8 'naloxone'/exp 35,728

#9 'pirinitramide'/exp 1,371










98

#10 'tramadol'/exp 10,829

#11 polamidone 25

#12 targin 29

#13 'heroin'/exp OR heroin 24,380

#14 'dihydrocodeine'/exp OR dihydrocodeine 2,037

#15 'nalbuphine'/exp OR nalbuphine 2,608

#16 'oxymorphone'/exp OR oxymorphone 1,509

#17 'tapentadol'/exp OR tapentadol AND ('hydrochloride'/exp OR hydrochloride) 23

#18 'diamorphine'/exp OR diamorphine 17,668

#19 'dihydrocodeine'/exp OR dihydrocodeine 2,037

#20 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12

OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

181,768

#21 'neoplasms'/exp 3,094,761

#22 'pain'/exp 693,916

#23 #20 AND #21 AND #22 5,645

#24 #23 AND ([adult]/lim OR [aged]/lim) AND [humans]/lim AND [1-12-2011]/sd 122

Cochrane Library

ID Search Hits

#1 MeSH descriptor Analgesics, Opioid explode all trees 4575

#2 MeSH descriptor Buprenorphine explode all trees 568

#3 MeSH descriptor Codeine explode all trees 903

#4 MeSH descriptor Dextropropoxyphene explode all trees 178

#5 MeSH descriptor Fentanyl explode all trees 3701

#6 MeSH descriptor Hydromorphone explode all trees 159

#7 MeSH descriptor Methadone explode all trees 826

#8 MeSH descriptor Morphine explode all trees 4426










99

#9 MeSH descriptor Naloxone explode all trees 1414

#10 MeSH descriptor Pirinitramide explode all trees 87

#11 MeSH descriptor Tramadol explode all trees 621

#12 polamidon OR polamidone OR targin 2

#13 MeSH descriptor Heroin explode all trees 237

#14 MeSH descriptor Nalbuphine explode all trees 177

#15 MeSH descriptor Oxymorphone explode all trees 42

#16 Diamorphine OR Dihydrocodeine OR "Tapentadol hydrochloride" 394

#17 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16)

11625





#22 (#17 AND ( ( #18 OR #19 ) AND ( #20 OR #21 ) )) 548

#23 (#22), in 2012 2

IPA/CINAHL

S11 S10 Limiters - Published Date from: 20111201-20120831; Human 21


S9 pain 121133

S8 S4 or S5 or S6 or S7 167507

S7 Tumour 29676

S6 Tumor 49148

S5 Cancer 132147

S4 Neoplasm 46264

S3 S1 or S2 16538

S2 Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride OR Nalbuphine

584

S1 buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR hydromorphone OR methadone OR morphine OR naloxone OR pirinitramide OR tramadol OR polamidon OR polamidone OR targin

16235


















100

BIOSIS

#13 #12 Databases=BIOSIS Previews Timespan=2012 Lemmatization=On

47

#12 #11 AND #8 AND #5 Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

2,297

#11 #10 OR #9 Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

223,754

#10 TS=(pain) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

223,754

#9 TI=(pain) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

62,930

#8 #7 OR #6 Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

2,781,310

#7 TS=(neoplasm OR cancer OR tumor OR tumour) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

2,781,310

#6 TI=(neoplasm OR cancer OR tumor OR tumour) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

771,702

#5 #4 OR #3 OR #2 OR #1 Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

95,234

#4

TI=(Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride OR Nalbuphine) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

720

#3

TS=(Diamorphine OR Dihydrocodeine OR Oxymorphone OR Tapentadol hydrochloride OR Nalbuphine) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

1,901

#2

TI=(buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR hydromorphone OR methadone OR morphine OR naloxone OR pirinitramide OR tramadol OR polamidon OR polamidone OR targin) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

42,757

#1

TS=(buprenorphine OR codeine OR dextropropoxyphene OR fentanyl OR hydromorphone OR methadone OR morphine OR naloxone OR pirinitramide OR tramadol OR polamidon OR polamidone OR targin) Databases=BIOSIS Previews Timespan=All Years Lemmatization=On

94,550

http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=17&SID=4AB6NckJ45lhhel35@M&search_mode=AdvancedSearch

http://apps.webofknowledge.com.libproxy.lib.unc.edu/summary.do?product=BIOSIS&doc=1&qid=16&SID=4AB6NckJ45lhhel35@M&search_mode=CombineSearches













101

Appendix B

Appendix-Table 1: Pharmaceutical Companies that were Contacted.

Marketing Authorization Holder Active Ingredient Country Received

Reply

ACINO AG Transdermal Buprenorphine Transdermal Fentanyl Oxycodone

Germany No

Actavis Morphine US Yes

Actavis Deutschland GmbH & Co Morphine Germany Yes

Actavis UK Ltd Transdermal Fentanyl Tramadol

UK No

Amdipharm Plc Morphine UK Yes

AWD.pharma GmbH & Co.

Hydromorphone Morphine Transdermal Buprenorphine Transdermal Fentanyl Tramadol

Germany Yes

BC Biochemie Pharma GmbH Morphine Germany No

Beechmere Pharmaceuticals Ltd Tramadol UK No

BERAGENA Arzneimittel GmbH/ Pharma Westen GmbH/ Grünenthal GmbH/ EMRA-MED Arzneimittel GmbH/ AxiCorp Pharma GmbH/ EurimPharm Arzneimittel GmbH/ Pharma Gerke Arzneimittelvertriebs GmbH/ kohlpharma GmbH

Tramadol Germany No

betapharm Arzneimittel GmbH

Transdermal Fentanyl Hydromorphone Morphine Oxycodone Tramadol

Germany No

Chiesi Limited Tramadol UK Yes

CIPHER PHARMS INC Tramadol US No

Dallas Burston Ashbourne Ltd Transdermal Fentanyl UK No

Endo Pharma Oxymorphone US No

Ethypharm Morphine Austria No

Ethypharm Morphine France No

Ethypharm Morphine Tramadol

Germany No

EurimPharm Arzneimittel GmbH Tramadol Germany No

EurimPharm Arzneimittel GmbH/ Mundipharma GmbH/ EurimPharm Arzneimittel GmbH

Tramadol Germany No

G. L. Pharma GmbH Morphine Oxycodone Dihydrocodeine

Austria Yes

Gebro Pharma AG Tramadol Switzerland No

GlaxoSmithKline AG Morphine Switzerland No

GlaxoSmithKline GmbH & Co. Morphine Germany Yes

GlaxoSmithKline Pharma GmbH Morphine Austria Yes

GRUENENTHAL GMBH Tramadol Austria No

Grünenthal GmbH

Transdermal Buprenorphine Morphine Tapentadol hydrochloride Tramadol

Germany No


102


Reply

Grünenthal Ltd Tapentadol hydrochloride Tramadol

UK No

Grünenthal Pharma AG Transdermal Buprenorphine Tramadol

Switzerland No

Halvepharm AG Morphine Switzerland No

Helm AG Transdermal Fentanyl Germany Yes

Hennig Arzneimittel GmbH & Co.KG Transdermal Fentanyl Germany Yes

Hexal AG Transdermal Fentanyl Austria No

HEXAL AG Hydromorphone Morphine Oxycodone

Germany Yes

Janssen - Cilag Pharma GmbH Hydromorphone Austria Yes

Janssen - Cilag Pharma GmbH Hydromorphone Germany No

Janssen Pharmaceuticals Tapentadol hydrochloride US No

Janssen-Cilag AG Transdermal Fentanyl Hydromorphone

Switzerland No

Janssen-Cilag Ltd Fentanyl UK No

Juta Pharma GmbH Morphine Tramadol

Germany Yes

King Pharms Morphine Morphine and naltrexone

US No

kohlpharma GmbH Dihydrocodeine Germany Yes

Krewel Meuselbach GmbH Transdermal Fentanyl Morphine Tramadol

Germany No

LABOPHARM EUROPE LTD, Tramadol Ireland Yes

Lannacher Heilmittel GmbH Morphine Tramadol

Austria No

LAVIPHARM S.A. Transdermal Fentanyl Greece No

Libra-Pharm GmbH Transdermal Buprenorphine Tramadol

Germany Yes

COVIDIEN Hydromorphone US No

MEDA Pharma GmbH Tramadol Switzerland Yes

MEDA Pharma GmbH & Co. KG Tramadol Germany No

Meda Pharmaceuticals Tramadol UK No

medac Gesellschaft für klinische Spezialpräparate mbH

Morphine Germany Yes

Merck Sharp & Dohme Limited Tramadol UK Yes

mibe GmbH Arzneimittel Transdermal Fentanyl Germany No

Morningside Livery Tramadol UK No

MUNDIPHARMA GMBH

Dihydrocodeine Hydromorphone Morphine Oxycodone Oxycodone + naloxone Tramadol

Austria Yes

Mundipharma GmbH


Germany Yes


103


Reply

Mundipharma GmbH/ PB Pharma GmbH Hydromorphone Germany Yes

Mundipharma Medical Company


Switzerland No

Napp Pharmaceuticals Limited

Transdermal Buprenorphine Dihydrocodeine hydromorphone Morphine Oxycodone Oxycodone + naloxone

UK No

NYCOMED DANMARK A/S, DK-ROSKILDE Transdermal Fentanyl Denmark No

Nycomed GmbH Transdermal Fentanyl Germany Yes

Nycomed Pharma AG Transdermal Fentanyl Switzerland No

Nycomed UK Ltd Transdermal Fentanyl UK Yes

Janssen Pharmaceuticals, Inc. Transdermal Fentanyl US No

Pfizer GmbH Morphine Germany No

PHARBIL PHARMA GMBH Hydromorphone Germany Yes

Pharmachemie B.V. Morphine Austria No

Purdue Pharma

Transdermal Buprenorphine Hydromorphone Morphine Oxycodone Tramadol

US Yes

Riemser Arzneimittel AG Transdermal Fentanyl Germany Yes

SMB TECHNOLOGY SA Tramadol Belgium Yes

Stadapharm GmbH

Transdermal Fentanyl Hydromorphone Morphine Oxycodone Tramadol

Germany Yes

TAD Pharma GmbH Transdermal Fentanyl Tramadol

Germany Yes

TEMMLER-PHARMA GMBH Tramadol Germany Yes

Teva Uk Limited Morphine UK No

Tillomed Laboratories Ltd Transdermal Fentanyl UK No

VALEANT INTL Tramadol US No

VEMEDIA MANUFACTURING B.V., Tramadol Netherlands No

Xanodyne Pharms Morphine US Yes

Yes Pharmaceutical Development Oxycodone Germany Yes


104

Appendix C

Abstract Review Form

Ref ID: ___________________________________________________________________

Reviewer Initials: _________

E1 Is the article primary research (no editorials, letters to the editor, narrative

reviews, etc.)?

Yes No

STOP !

Cannot

determine

E2 Is the study population of interest for the review:

Adult patients with

moderate or severe cancer-related pain of any aetiology (primary or secondary malignancy from solid or haematological tumours)

Yes No

STOP !

Cannot

determine

E3 Does the study compare any of the following extended-release opioids (or

combinations) with another extended-release opioid:

Transdermal Buprenorphine

Codeine

Dihydrocodeine

Transdermal Fentanyl

Hydromorphone

Morphine

Nalbuphine

Oxycodone

Oxymorphone

Tapentadol hydrochloride

Tramadol

Morphine + Naltrexone

Oxycodone + Naloxone

Yes No

STOP !

Cannot

determine

E4 Are the opioids investigated in the study:

oral or

transdermal extended-release opioids

Yes No

STOP !

Cannot

determine

E5 Is the study answering 1 of the key questions of the review (see protocol and

next page)?

Yes No

STOP !

Cannot

determine

E6 Is the study design eligible for the review:

Head-to-head RCTs of ≥ 1 week

Observational studies of ≥ 1 week (n ≥ 100)

Systematic reviews or meta-analyses

Yes No

STOP !

Cannot

determine

Should the abstract be included?

(If you have checked “No” for any of the questions, abstract should be

excluded)

Yes No

Second Reviewer Initials: _________

Should the abstract be included? Yes No Cannot

determine

Should the article be included as background literature? Yes


105

Please start from the beginning and take the first reason of exclusion that applies.

Fulltext Review Form

Is the publication original research (NOT

editorials, letters to the editor, non-

systematic reviews, case-reports, case series)?

NO 1. Wrong Publication Type

Is it a randomized controlled trial, a non-

randomized controlled trial with at least 100

participants or a systematic review +/- meta-

analysis?

NO 2. Wrong Study Design

Was the intervention administered at least 1

week (7 days)?

NO 3. Wrong Duration

Are participants at least 18 years old?

AND

Have moderate to severe cancer-related

pain?

NO 4. Wrong Population

Is the intervention an extended-release opioid

from the list?

NO 5. Wrong Intervention

Is the intervention administered orally or

transdermally

NO 6. Wrong Administration

Is there an appropriate comparator

(extended-release or immediate opioid or

placebo)?

NO 7. Wrong Comparator

Is at least 1 outcome of interest reported? NO 8. Wrong Outcome

Does the study address 1 of our key

questions?

NO 9. Wrong Research Question

Is the language of the article English or

German?

NO 10. Wrong Language

Is the fulltext available? NO 11. Fulltext not available

Is the article available as fulltext? NO 12. Only Abstract

If no exclusion code applies or you need more information to decide, mark “INCLUDE”


106

Appendix D

Appendix-Table 2: High Risk of Bias Studies and Reasons for the Poor Quality Rating.

Study Design Reasons for High Risk of Bias Rating

Ahmedzai et al., 2012(41) RCT Pseudo-random number generator for randomization; partial ITT analysis; 28% attrition (27% and 28%)


RCT 30% attrition; no ITT analysis; unclear risk for selection bias

Hanna et al., 2008(42) RCT 33.5% attrition (39.4% and 27.7%); unclear risk of selection bias


RCT Non-blinded study; 35.2% attrition (38.9% and 30.6%); no ITT analysis

Okamoto et al., 2010(47) Retrospective cohort study

Retrospective design; no information on duration of follow-up, opioid doses, blinding, outcome measures


RCT Non-blinded study; 39% attrition (55% and 24%); no ITT analysis

Abbreviations: ITT, intent to treat analysis; RCT, randomized controlled trial.


107

Appendix E

Appendix-Table 3: KQ1: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Hydromorphone ER, sorted by Outcomes for KQ1.

Number of Studies, Study Designs

Sample Size Risk of Bias Inconsistency Indirectness Imprecision Other Considerations

Quality of Evidence

Importance of Outcome

Pain Intensity (BPI 0-10)

1, head-to-head RCT, Hanna et al. 2008(42)


Serious risk of bias1 Not

applicable2

No serious indirectness

Very serious imprecision

3

None VERY LOW

CRITICAL

Quality of Life (BPI interference scale)




applicable2



3

None VERY LOW

CRITICAL

Patient Perceived Effectiveness




applicable2



3

None VERY LOW

CRITICAL

Abbreviations: BPI, brief pain inventory; ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; h, hour; IR, immediate-release; KQ, Key Question; NR, not reported; RCT, randomized controlled trial

1 High attrition (33.5%), unclear risk of selection bias. Rated down.

2 Single study for this comparison.

3 No confidence interval reported. Rated down two levels.


108

Appendix-Table 4: KQ1: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Oral Oxycodone ER, sorted by Outcomes for KQ1.



Quality of Evidence


Pain Intensity (VAS 0-100mm)

1, head-to-head RCT, Hagen and Babul, 1997(40)

44 Serious risk of bias1 Not

applicable2



3

None VERY LOW

CRITICAL

Abbreviations: ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KQ, Key Question; RCT, randomized controlled trial; VAS, visual analogue scale

1 High attrition (30%), no intention-to-treat analysis, unclear risk for selection bias. Rated down.




109

Appendix-Table 5: KQ1: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Oxycodone plus Naloxone ER, sorted by Outcomes for KQ1.



Quality of Evidence


Pain Intensity (BPI-SF)

1, head-to-head RCT, Ahmedzai et al., 2012(41)


applicable2



3

None VERY LOW

CRITICAL

Quality of Life (EuroQoL EQ-5D)



applicable2



3

None VERY LOW

CRITICAL

Abbreviations: BPI-SF, brief pain inventory-short form; EuroQoL EQ-5D, European Quality of Life Instrument; ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KQ, Key Question; RCT, randomized controlled trial; QoL, quality of life;

1 High attrition (28%), only partial intention-to-treat analysis, use of a pseudo-random number generator for randomization, per-protocol analysis for some of the outcomes. Rated down.




110

Appendix-Table 6: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Hydromorphone ER, sorted by Outcomes for KQ2.



Quality of Evidence


Serious Adverse Events




applicable2



3

None VERY LOW

CRITICAL

Constipation



Serious risk of bias1 Serious

inconsistency4



5

None

VERY LOW

CRITICAL 1, prospective cohort study Wirz et al. 2008(45)

100 No serious risk of bias

6

Nausea and Vomiting



Serious risk of bias1 Serious

inconsistency4



5

None

VERY LOW

CRITICAL 1, prospective cohort study, Wirz et al. 2008(45)


6

Abbreviations: ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; IR, immediate-release; KQ, Key Question; RCT, randomized controlled trial;

1 High overall attrition for the IR phase (33.5%), unclear risk of selection bias. Rated down.



4 Different results according to different outcome measures in one observational study. Inconsistent results between RCT and observational study. Rated down.


6 Different time spans of using opioids before entering the study and lack of blinding of outcome assessment, lack of adjustment for confounding.


111

Appendix-Table 7: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Oral Oxycodone ER, sorted by Outcomes for KQ2.



Quality of Evidence



1, retrospective cohort study, Hartung et al. 2007(48)


1

Not applicable

2


Serious imprecision

3

None VERY LOW

CRITICAL

Constipation

1, retrospective cohort study, Hartung et al. 2007(48)


1

Not applicable

2


Serious imprecision

3

None VERY LOW

CRITICAL

Nausea and Vomiting

1, retrospective cohort study, Okamoto et al., 2010(47, 48)

226 Very serious risk of bias

4

Not applicable

2


Serious imprecision

5

None VERY LOW

CRITICAL

Abbreviations: ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KQ, Key Question;

1 No blinding of outcome assessment, no valid and reliable outcome measures.


3 Event rate below optimal information size; confidence intervals cross clinically important thresholds. Rated down.

4 Exclusion of participants, no comment about time to follow-up in all study groups, no information about opioid-doses. Rated down two levels.

5 Event rate below optimal information size; No confidence interval reported; Rated down.


112

Appendix-Table 8: KQ2: GRADE Ratings for the Comparison Oral Morphine ER vs. Transdermal Fentanyl ER, sorted by Outcomes For KQ2.


Sample Size

Risk of Bias Inconsistency Indirectness Imprecision Other Considerations

Quality of Evidence



1, head-to head RCT(44) van Seventer et al. 2003(44)

131 Serious risk of bias1 No serious

inconsistency No serious indirectness

Serious imprecision

2

None

LOW

CRITICAL 1, retrospective cohort study, Hartung et al. 2007(48)


3

Constipation

2, head-to-head RCT, Mercadante et al. 2008(43), van Seventer et al. 2003(44)

203 Serious risk of bias4 No serious

inconsistency No serious indirectness

Serious imprecision

5

None

LOW

CRITICAL 1, retrospective cohort study, Hartung et al. 2007(48)


3

Nausea and Vomiting

2, head-to-head RCT, Mercadante et al. 2008(43), van Seventer et al. 2003(44)

203 Serious risk of bias4 Serious

inconsistency6



7

None

VERY LOW

CRITICAL 1, retrospective cohort study, Okamoto et al. 2010(47)


8

Abbreviations: ER, extended-release; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KQ, Key Question; RCT, randomized controlled trial;

1 Lack of blinding of participants and personnel as well as outcomes assessors, high attrition (van Seventer (48) et al.: 39%) and lack of intention-to-treat-analyses. Rated down.

2 Studies do not meet optimal information size; wide confidence intervals for all estimates, Rated down.

3 No blinding of outcome assessment, no valid and reliable outcome measures.

4 Lack of blinding of participants and personnel as well as outcomes assessors, high attrition (van Seventer et al. 44. 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. Epub 2003/11/05.: 39%; Mercadante et al. 28: 35,2%) and lack of intention-to-treat-analyses. Rated down. 5 No confidence interval reported for RCTs; Confidence intervals for cohort study cross clinically important thresholds. Rated down.

6 Inconsistent results. Rated down.

7 Event rate below optimal information size; No confidence interval reported. Rated down two levels.

8 Exclusion of participants, No comment about time to follow-up in all study groups, no information about opioid-doses . Rated down two levels.


113

Appendix-Table 9: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Oral Oxycodone ER sorted by Outcomes for KQ2.


Sample Size Risk Of Bias Inconsistency Indirectness Imprecision Other Considerations

Quality of Evidence



No evidence CRITICAL

Constipation

No evidence CRITICAL

Nausea and Vomiting

1, head-to-head RCT, Hagen and Babul, 1997(40)


applicable2


Very serious Imprecision

3

None VERY LOW

CRITICAL


1 High attrition (30%), no intention-to-treat analysis, unclear risk for selection bias. Rated down.




114

Appendix-Table 10: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Transdermal Fentanyl ER, sorted by Outcomes for KQ2.



Quality of Evidence



No Evidence CRITICAL

Constipation

1, prospective cohort study, Wirz et al. 2009(46)


1

Serious inconsistency

2



3

None

VERY LOW

CRITICAL

Nausea and Vomiting



1


4



3

None VERY LOW

CRITICAL


1 Different time spans of using opioids before entering the study and lack of adequate adjustment for confounding.

2 Different outcome-measures for each endpoint with inconsistent results. Rated down.


4 Vomiting: Different outcome-measures with inconsistent results. Rated down.


115

Appendix-Table 11: KQ2: GRADE Ratings for the Comparison Oral Hydromorphone ER vs. Transdermal Buprenorphine ER, sorted by Outcomes for KQ2.


Sample size Risk of Bias Inconsistency Indirectness Imprecision Other Considerations

Quality of Evidence




Constipation

1, prospective cohort study, Wirz et al. 2009 (46)


1


2



3

None VERY LOW

CRITICAL

Nausea and Vomiting

1, prospective cohort study, Wirz et al. 2009 (46)


1


4



3

None VERY LOW

CRITICAL



2 Different outcome-measures for each endpoint with inconsistent results in one observational study. Rated down.


4 Vomiting: Different outcome-measures with inconsistent results. Rated down.


116

Appendix-Table 12: KQ2: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Oral Oxycodone ER + Naloxone, sorted by Outcomes for KQ2.



Quality of Evidence





applicable2



3

None VERY LOW

CRITICAL

Constipation



applicable2


Serious imprecision

4

None LOW

CRITICAL

Nausea and Vomiting



applicable2



3

None VERY LOW

CRITICAL


1 Lack of random sequence generation and high attrition rates (27,7%) and only partial intention-to-treat analysis. Rated down.



4 Confidence interval for primary outcome cross clinically important thresholds. Rated down.


117

Appendix-Table 13: KQ2: GRADE Ratings for the Comparison Oral Oxycodone ER vs. Transdermal Fentanyl ER, sorted by Outcomes for KQ2.



Quality of Evidence




Constipation


Nausea and Vomiting

1, retrospective cohort study, Okamoto et al. 2010(47)


1

Not applicable

2


No serious imprecision

3

None VERY LOW

CRITICAL


1 Exclusion of participants, no comment about time to follow-up in all study groups, no information about opioid-doses. Rated down two levels.


3Confidence Interval based on internal calculations shows clear risk of nausea for oxycodone, wide confidence interval.


118

Appendix-Table 14: KQ2: GRADE Ratings for the Comparison Transdermal Fentanyl ER vs. Transdermal Buprenorphine ER, sorted by Outcomes For KQ2.



Quality of Evidence




Constipation



1

Not applicable

2



3

None VERY LOW

CRITICAL

Nausea and Vomiting



1

Not applicable

2



3

None VERY LOW

CRITICAL






119

Appendix F

Appendix-Table 15: Commonly Used Outcome Measures and Instruments.

Abbreviated Name

Complete Name Description Range/Meaning of Possible Scores

Improvement Indicated by

BPI Brief Pain Inventory

32-item self-administered questionnaire for patients with cancer pain or pain due to other chronic diseases. It assesses intensity of pain (severity) and the interference of pain on daily functions like general activity, walking, work, mood, enjoyment of life, relations with others, and sleep. It asks patients to rate their pain at the time of responding to the questionnaire, and additionally also at its worst, least, and average over the past week. Assessment takes 10 minutes.

Rating of pain: 0 = no pain, 10 = pain as bad as you can imagine Rating of interference of pain: 0 = no interference, 10 = complete interference

decrease

BPI-SF Brief Pain Inventory- Short Form

9-item self-administered questionnaire for patients with cancer pain or pain due to other chronic diseases. It assesses intensity of pain (severity) and the interference of pain on daily functions like general activity, walking, work, mood, enjoyment of life, relations with others, and sleep. It asks patients to rate their pain at the time of responding to the questionnaire, and additionally also at its worst, least, and average over the last 24h. Assessment takes 5 minutes.

Rating of pain: 0 = no pain, 10 = pain as bad as you can imagine Rating of interference 0 = no interference, 10 = complete interference

decrease

VAS 0-100mm

Visual Analogue Scale

Tool for measuring subjective phenomena such as pain. The patient marks a point on a 10 cm long line that begins with “no pain” and ends with “worst imaginable pain”. This point matches the amount of pain he/she feels.

0 = no pain 100 = worst imaginable pain

decrease


120

Abbreviated Name

Complete Name Description Range/Meaning of Possible Scores

Improvement Indicated by

EuroQoL EQ-5D

European Quality of Life Questionnaire

Self-classifier system to describe the respondent's own health in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents can value their health in each dimension at three ordinal levels. The second measurement component is a 20 cm vertical Visual Analogue Scale to rate the current health status. Takes a few minutes to complete.

1= no problem 2 = moderate problems 3= severe or extreme problems

decrease

MMSE Mini-Mental State Examination

30-point questionnaire test that is used to screen for cognitive impairment. It tests five areas of cognitive function: orientation, registration, attention and calculation, recall and language. It estimates the severity of cognitive impairment at a specific time and can measure cognitive changes in an individual over time. Time frame for assessment: 10 minutes.

MMSE scores (0-30); higher scores indicate better cognitive performance

increase

NRS Numerical Rating Scale

Self-reported, 11-point, fixed-interval scale used for the subjective measurement of clinical signs or a syndrome (e.g., pain), in which numerical scores are given. A description is given for each score. The patient chooses the score on a scale from 0-10 (no symptom – worst symptom imaginable) indicating his/her level of pain.

0 = no symptom, 10 = worst symptom imaginable

decrease

EORTC QLQ-C30

European Organization For Research and Treatment Of Cancer QOL Core Questionnaire 30 (Item on nausea and vomiting)

30-item, self-reporting questionnaire to assess the quality of life of cancer patients. It is grouped into five functional subscales (role, physical, cognitive, emotional and social functioning), a global health status scale, three symptom scales (fatigue, pain, and nausea and vomiting) as well as individual questions concerning common symptoms in cancer patients. The Core Questionnaire can be supplemented by diseases specific modules. Time frame for assessment: 10-20 minutes.

1=not at all, 2=a little, 3=quite a bit, 4=very much; can be transformed to scores ranging from 0-100 Functional scales: higher score means high level of functioning QOL: higher score means high QOL Symptoms scales: higher score means high level of symptomatology

Functional scale: increase QOL Scale: increase Symptoms scales: decrease Clinically significant: Change of at least 10 points


121

Appendix G

Commonly Used Abbreviations

Abbreviation Description

AE Adverse Events

BFI Bowel Function Index

BPI Brief Pain Inventory

BPI-SF Brief Pain Inventory-Short Form

CI Confidence Interval

d Day

ED Emergency Department

EORTC QLQ 30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30

ER Extended-Release

EuroQoL EQ-5D European Quality of Life Instrument

h Hours

HR Hazard Ratio

ICD International Classification of Diseases

IR Immediate-Release

KQ Key Question

mg Milligram

MMSE Mini-Mental State Examination

n Number of Participants

NR Not Reported

NRS Numerical Rating Scale

OR Odds Ratio

p Probability

PAC-SYM Patient Assessment of Constipation Symptoms

QoL Quality of Life

RCT Randomized Controlled Trial

SAE Serious Adverse Events

SD Standard Deviation

SR Sustained-Release

VAS Visual Analogue Scale

vs. Versus

μg Microgram


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Appendix H

Excluded studies

Ineligible Publication Type (19):

1. Caraceni A, Pigni A, Brunelli C. Is oral morphine still the first choice opioid for moderate to severe cancer pain? A systematic review within the European Palliative Care Research Collaborative guidelines project. Palliative medicine. 2011;25(5):402-409.

2. Chwieduk CM, McKeage K. Fentanyl sublingual: in breakthrough pain in opioid-tolerant adults with cancer. Drugs. 2010;70(17):2281-2288.

3. Comerford T, Bruera E. Efficacy of controlled-release oxycodone [5] (multiple letters). Journal of Clinical Oncology. 1999;17(2):738.

4. Cormie PJ, Nairn M, Welsh J, Guideline Dev G. Control of pain in adults with cancer: summary of SIGN guidelines. British Medical Journal (England). 2008;337(NOV 5):NIL-NIL.

5. Gordon DB. Journal club. Oral transmucosal fentanyl citrate for cancer breakthrough pain: a review. Oncology nursing forum. 2006;33(2):257-264.

6. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncology. 2001;2(3):165-172.

7. Hair PI, Keating GM, McKeage K. Transdermal matrix fentanyl membrane patch (MATRIFEN): in severe cancer-related chronic pain. Drugs. 2008;68(14):2001-2009.

8. Hoy SM, Keating GM. Fentanyl Transdermal Matrix Patch (DUROTEP MT patch; DUROGESIC DTRANS; DUROGESIC SMAT): in adults with cancer-related pain. Drugs. 2008;68(12):1711-1721.

9. King S, Forbes K, Hanks G, Ferro C, Chambers E. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: A European Palliative Care Research Collaborative opioid guidelines project. Palliative medicine. 2011;25(5):525-552.

10. King SJ, Reid C, Forbes K, Hanks G. A systematic review of oxycodone in the management of cancer pain. Palliative medicine. 2011;25(5):454-470.

11. Klepstad P, Kaasa S, Borchgrevink PC. Starting Step III opioids for moderate to severe pain in cancer patients: Dose titration: A systematic review. Palliative medicine. 2011;25(5):424-430.

12. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Carr D, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. Journal of Pain (USA). 2003;4(May):231-256.

13. Pigni A, Brunelli C, Caraceni A. The role of hydromorphone in cancer pain treatment: a systematic review. Palliative medicine. 2011;25(5):471-477.

14. Ruiz-Garcia V, Lopez-Briz E. Breakthrough cancer pain: morphine remains gold standard in breakthrough cancer pain. BMJ: British Medical Journal (Overseas & Retired Doctors Edition). 2009;338(7685):7-8.

15. Tassinari D, Drudi F, Rosati M, Tombesi P, Sartori S, Maltoni M. The second step of the analgesic ladder and oral tramadol in the treatment of mild to moderate cancer pain: A systematic review. Palliative medicine. 2011;25(5):410-423.

16. Twycross RG. Controlled release morphine tablets. Lancet (England). 1981;1(Apr 18):892.

17. Vissers D, Stam W, Nolte T, Lenre M, Jansen J. Efficacy of intranasal fentanyl spray versus other opioids for breakthrough pain in cancer. Vol 26:1037.


123

18. Xu GZ, Cai ZJ, Deng YP, Hou J, Liu SJ, Et. Clinical evaluation of the analgesic effect of sustained-release morphine sulfate microgranules in patients with terminal cancer. Clinical Drug Investigation (New Zealand). 1997;14(Suppl 1):34-42.

19. Yu S, Sun Y. A large-scale study of OxyContin® tablets for relieving moderate to severe cancer pain. European Journal of Pain Supplements. 2007;1(1):99-100.

Ineligible Study Design (36):

1. 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. May 1997;13(5):254-261.

2. Anonymous. Abstral(R) (Fentanyl Sublingual Tablets for Breakthrough Cancer Pain). Vol 36:2.

3. Beaver WT, Wallenstein SL, Rogers A, Houde RW. Analgesic studies of codeine and oxycodone in patients with cancer. I. Comparisons of oral with intramuscular codeine and of oral with intramuscular oxycodone. J Pharmacol Exp Ther. Oct 1978;207(1):92-100.

4. Brooks I, De Jager R, Blumenreich M, George E, Savarese JJ. PRINCIPLES OF CANCER PAIN MANAGEMENT USE OF LONG-ACTING ORAL MORPHINE. Journal of Family Practice. 1989;28(3):275-280.

5. Chen HP, Jiang JJ, Li JX. Efficacy and safety of oxycodone-acetaminophen for moderate and severe visceral pain in advanced cancer patients. Vol 18:920.

6. Clark AJ, Ahmedzai SH, Allan LG, et al. Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic non-cancer pain. Curr Med Res Opin. Sep 2004;20(9):1419-1428.

7. Clemens KE, Klaschik E. Clinical experience with transdermal and orally administered opioids in palliative care patients--a retrospective study. Jpn J Clin Oncol. Apr 2007;37(4):302-309.

8. De Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. Journal of Pain and Symptom Management. 1995;10(5):378-384.

9. Gamallo A, Monescillo MA, Pereira MA, et al. Transdermal fentanyl for the treatment of chronic cancer pain in patients under home palliative care. European Journal of Cancer. Sept. 1999;35(SUPPL. 4):S368.

10. Grond S, Radbruch L, Meuser T, Loick G, Sabatowski R, Lehmann KA. High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage. Sep 1999;18(3):174-179.

11. Hanna M, Tuca A, Thipphawong J. An open-label, 1-year extension study of the long-term safety and efficacy of once-daily OROS1 hydromorphone in patients with chronic cancer pain. BMC Palliative Care. 2009;8.

12. Hays H, Hagen N, Thirlwell M, et al. Comparative clinical efficacy and safety of immediate release and controlled release hydromorphone for chronic severe cancer pain. Cancer. Sep 15 1994;74(6):1808-1816.

13. Kanamori C, Kanamori T, Hayashi M, Yorioka H, Kanzaki H. Three-cycle fentanyl patch system significantly improves pain control in gynecologic cancer. Journal of Obstetrics & Gynaecology Research. 2006;32(6):605-609.

14. Khojasteh A, Evans W, Reynolds RD, Thomas G, Savarese JJ. Controlled-release oral morphine sulfate in the treatment of cancer pain with pharmacokinetic correlation. J Clin Oncol. Jun 1987;5(6):956-961.

15. Lauretti GR, Oliveira GM, Pereira NL. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. Dec 1 2003;89(11):2027-2030.


124

16. Leelanuntakit S. Management of cancer-related pain with transdermal fentanyl. J Med Assoc Thai. Jun 1996;79(6):341-346.

17. 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.

18. Leppert W, Majkowicz M. The impact of tramadol and dihydrocodeine treatment on quality of life of patients with cancer pain. Int J Clin Pract. Nov 2010;64(12):1681-1687.

19. Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: A prospective, age-group-controlled study. Clinical therapeutics. 2006;28(12):2022-2039.

20. 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 Clin Oncol. Nov 1998;16(11):3656-3661.

21. Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol. Aug 1 2005;23(22):5229-5234.

22. Mercadante S, Tirelli W, David F, et al. Morphine versus oxycodone in pancreatic cancer pain: a randomized controlled study. Clin J Pain. Nov-Dec 2010;26(9):794-797.

23. Miyazaki T, Hanaoka K, Namiki A, et al. Efficacy, safety and pharmacokinetic study of a novel fentanyl-containing matrix transdermal patch system in Japanese patients with cancer pain. Clinical drug investigation. 2008;28(5):313-325.

24. Morita T, Takigawa C, Onishi H, et al. Opioid rotation from morphine to fentanyl in delirious cancer patients: an open-label trial. Journal of Pain & Symptom Management. 2005;30(1):96-103.

25. Pace MC, Passavanti MB, Grella E, et al. Buprenorphine in long-term control of chronic pain in cancer patients. Front Biosci. 2007;12:1291-1299.

26. Panich A, Charnvej L. Comparison of morphine slow release tablet (MST) and morphine sulphate solution (MSS) in the treatment of cancer pain. J Med Assoc Thai. Dec 1993;76(12):672-676.

27. Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol. Apr 1998;16(4):1588-1593.

28. Reid CM, Martin RM, Sterne JA, Davies AN, Hanks GW. Oxycodone for cancer-related pain - Meta-analysis of randomized controlled trials. Archives of Internal Medicine (USA). 2006;166(Aug):837-843.

29. Salzman RT, Roberts MS, Wild J, Fabian C, Reder RF, Goldenheim PD. Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control? J Pain Symptom Manage. Oct 1999;18(4):271-279.

30. Sittl R, Nuijten M, Nautrup BP. Changes in prescribed daily doses of transdermal fentanyl and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study. Clinical therapeutics. 2005;27(7):1022-1031.

31. Sloan P, Slatkin N, Ahdieh H. Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: a pilot study. Support Care Cancer. Jan 2005;13(1):57-65.

32. Ventaffrida V, Oliveri E, Caraceni A, et al. A retrospective study on the use of oral morphine in cancer pain. J Pain Symptom Manage. Spring 1987;2(2):77-81.

33. Weinstein SM, Messina J, Xie F. Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain in Opioid-Tolerant Patients With Chronic Cancer Pain: A Long-term, Open-Label Safety Study. (vol 115, pg 2571, 2009). Cancer. Jul 15 2009;115(14):3372.


125

34. Weinstein SM, Shi M, Buckley BJ, Kwarcinski MA. Multicenter, open-label, prospective evaluation of the conversion from previous opioid analgesics to extended-release hydromorphone hydrochloride administered every 24 hours to patients with persistent moderate to severe pain. Clin Ther. Jan 2006;28(1):86-98.

35. Wilkinson TJ, Robinson BA, Begg EJ, Duffull SB, Ravenscroft PJ, Schneider JJ. Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients. Cancer Chemother Pharmacol. 1992;31(3):251-254.

36. Wong JO, Chiu GL, Tsao CJ, Chang CL. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Acta Anaesthesiol Sin. Mar 1997;35(1):25-32.

Ineligible Duration (22):

1. Bono AV, Cuffari S. Efficacy and tolerability of tramadol in neoplastic pain: A comparative study with buprenorphine. Drugs. 1997;53(SUPPL. 2):40-49.

2. Chrubasik S, Friedrich G, Yucel A, Aykut G, Chrubasik J, Ziegler R. Replacement of oral slow release morphine by morphine sulphate suppositories in patients suffering from intractable cancer pain. Regional Anesthesia. 1997;22(2 SUPPL.):102.

3. Cundiff D, McCarthy K, Savarese JJ, et al. Evaluation of a cancer pain model for the testing of long-acting analgesics. The effect of MS Contin in a double-blind, randomized crossover design. Cancer. Jun 1 1989;63(11 Suppl):2355-2359.

4. Finn JW, Walsh TD, MacDonald N, Bruera E, Krebs LU, Shepard KV. Placebo-blinded study of morphine sulfate sustained-release tablets and immediate-release morphine sulfate solution in outpatients with chronic pain due to advanced cancer. J Clin Oncol. May 1993;11(5):967-972.

5. Grosset AB, Roberts MS, Woodson ME, et al. Comparative efficacy of oral extended-release hydromorphone and immediate-release hydromorphone in patients with persistent moderate to severe pain: two randomized controlled trials. J Pain Symptom Manage. Jun 2005;29(6):584-594.

6. Hanks GW, Twycross RG, Bliss JM. Controlled release morphine tablets: a double-blind trial in patients with advanced cancer. Anaesthesia. Aug 1987;42(8):840-844.

7. Heiskanen T, Kalso E. Controlled-release oxycodone and morphine in cancer related pain. Pain. Oct 1997;73(1):37-45.

8. Heiskanen TE, Ruismaki PM, Seppala TA, Kalso EA. Morphine or oxycodone in cancer pain? Acta Oncol. 2000;39(8):941-947.

9. Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther. May 1990;47(5):639-646.

10. Mercadante S, Arcuri E, Fusco F, et al. Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain. Support Care Cancer. Sep 2005;13(9):702-707.

11. Moertel CG, Ahmann DL, Taylor WF, Schwartau N. Relief of pain by oral medications: a controlled evaluation of analgesic combinatioms. J. Am. Med. Assoc. 1974;229(Jul 1):55-59.

12. 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 Clin Pharmacol. Jun 2000;56(3):219-223.

13. Mucci-LoRusso P, Berman BS, Silberstein PT, et al. Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: A randomized, double-blind, parallel-group study. European Journal of Pain. 1998;2(3):239-249.


126

14. Parris WC, Johnson BW, Jr., Croghan MK, et al. The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study. J Pain Symptom Manage. Oct 1998;16(4):205-211.

15. Savarese JJ, Thomas GB, Homesley H, Hill CS. Rescue factor: design for evaluating long acting analgesics. Clinical Pharmacology and Therapeutics (USA). 1988;43(Apr):376-380.

16. Sawe J, Dahlstrom B, Rane A. Steady-state kinetics and analgesic effect of oral morphine in cancer patients. Eur J Clin Pharmacol. 1983;24(4):537-542.

17. 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 Clin Pharmacol. May 2001;41(5):500-506.

18. Staquet M. Double blind study of dezocine in cancer pain. Journal of Clinical Pharmacology (USA). 1979;19(Jul):392-394.

19. Walsh TD. A controlled study of MST Continuos tablets for chronic pain in advanced cancer. Advances in Morphine Therapy. the 1983 International Symposium on Pain Control. 1984:99-102.

20. 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. Feb 1994;5(2):141-146.

21. Wirz S, Wartenberg HC, Elsen C, Wittmann M, Nadstawek J, et al. Managing cancer pain and symptoms of outpatients by rotation to sustained-release hydromorphone - A prospective clinical trial. Clinical Journal of Pain. 2006;22(Sep):770-775.

22. Zech D, Dauer HG, Stollenwerk B, Lehmann KA. PCA AND TTS FENTANYL IN THE TREATMENT OF CANCER PAIN. Pain. 1990(SUPPL. 5):S356.

Ineligible Population (11):

1. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: Systematic review and meta-analysis of randomized controlled trials. Journal of the American Medical Association. 2005;293(24):3043-3052.

2. Galer BS, Lee D, Ma T, Nagle B, Schlagheck TG. MorphiDex® (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: Three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain. 2005;115(3):284-295.

3. Mayyas F, Fayers P, Kaasa S, Dale O. A systematic review of oxymorphone in the management of chronic pain. Journal of Pain & Symptom Management. 2010;39(2):296-308.

4. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain. Feb 1999;79(2-3):303-312.

5. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database of Systematic Reviews. 2002(1).

6. Sidebotham D, Dijkhuizen MRJ, Schug SA. The safety and utilization of patient-controlled analgesia. Journal of Pain & Symptom Management. 1997;14(4):202-209.

7. Sittl R, Griessinger N, Likar R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. Jan 2003;25(1):150-168.


127

8. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. Nov 2004;26(11):1808-1820.

9. Tassinari D, Sartori S, Tamburini E, et al. Transdermal fentanyl as a front-line approach to moderate-severe pain: a meta-analysis of randomized clinical trials. Journal of Palliative Care. 2009;25(3):172-180.

10. Zeppetella G. Opioids for the management of breakthrough cancer pain in adults: A systematic review undertaken as part of an EPCRC opioid guidelines project. Palliative medicine. 2011;25(5):516-524.

11. Zhao SZ, Chung F, Hanna DB, Raymundo AL, Cheung RY, Chen C. Dose-response relationship between opioid use and adverse effects after ambulatory surgery. Journal of Pain & Symptom Management. 2004;28(1):35-46.

Ineligible Intervention (23):

1. Anonymous. Fentanyl Buccal Soluble Film (<it>Onsolis</it>) for Breakthrough Cancer Pain. Vol 52:30.

2. Arbaiza D, Vidal O. Tramadol in the treatment of neuropathic cancer pain: a double-blind, placebo-controlled study. Clin Drug Investig. 2007;27(1):75-83.

3. Bruera E, Belzile M, Pituskin E, et al. Efficacy and safety of morphine sulfate controlled-release suppositories (MS-CRS) administered once daily and twice daily for severe cancer pain. Journal of Palliative Care. Fal 1998;14(3):117-117.

4. Chary S, Goughnour BR, Moulin DE, Thorpe WR, Harsanyi Z, Darke AC. The dose-response relationship of controlled-release codeine (Codeine Contin) in chronic cancer pain. J Pain Symptom Manage. Aug 1994;9(6):363-371.

5. Clemons M, Regnard C, Appleton T. Alertness, cognition and morphine in patients with advanced cancer. Cancer Treatment Reviews. 1996;22(6):451-468.

6. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. Mar 2001;91(1-2):123-130.

7. De Conno F, Ripamonti C, Sbanotto A, et al. A clinical study on the use of codeine, oxycodone, dextropropoxyphene, buprenorphine, and pentazocine in cancer pain. Journal of Pain & Symptom Management. 1991;6(7):423-427.

8. Dhaliwal HS, Sloan P, Arkinstall WW, et al. Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain. J Pain Symptom Manage. Nov 1995;10(8):612-623.

9. Ferrell B, Wisdom C, Wenzl C, Brown J. Effects of controlled-released morphine on quality of life for cancer pain. Oncol Nurs Forum. Jul-Aug 1989;16(4):521-526.

10. Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. Jun 1986;25(3):297-312.

11. Kanner RM, Foley KM. Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci. 1981;362:161-172.

12. Marinangeli F, Ciccozzi A, Leonardis M, et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage. May 2004;27(5):409-416.

13. Reid. Oxycodone for cancer-related pain: Meta-analysis of randomized controlled trials (vol 166, pg 837, 2006). Archives of internal medicine. Nov 27 2006;166(21):2387.


128

14. Rodriguez RF, Bravo LE, Castro F, et al. Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial. J Palliat Med. Feb 2007;10(1):56-60.

15. Rodriguez RF, Castillo JM, Castillo MP, et al. Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: a double-blind comparative trial. Clin J Pain. Jan 2008;24(1):1-4.

16. Rodriguez RF, Castillo JM, Del Pilar Castillo M, et al. Codeine/acetaminophen and hydrocodone/acetaminophen combination tablets for the management of chronic cancer pain in adults: a 23-day, prospective, double-blind, randomized, parallel-group study. Clin Ther. Apr 2007;29(4):581-587.

17. Rodriguez RF, Castillo JM, Mdp C. Codeine/paracetamol and hydrocodone/paracetamol combination tablets for the management of chronic cancer pain in adults: A 23-days, prospective, double-blind, randomized, parallel-group study. Clin Ther. 2007;29:582-587.

18. Stambaugh JE, Jr., McAdams J. Comparison of the analgesic efficacy and safety oral ciramadol, codeine, and placebo in patients with chronic cancer pain. J Clin Pharmacol. Feb 1987;27(2):162-166.

19. Twycross RG. Choice of strong analgesic in terminal cancer: diamorphine or morphine? Pain. 1977(2):93-104. http://www.mrw.interscience.wiley.com/cochrane/clcentral/articles/312/CN-00016312/frame.html.

20. Twycross RG. Comparison of diamorphine with cocaine and methadone. British Journal of Clinical Pharmacology (England). 1977;4(Dec):691-693.

21. Ventafridda V, De Conno F, Guarise G, Tamburini M, Savio G. Chronic analgesic study on buprenorphine action in cancer pain. Comparison with pentazocine. Arzneimittelforschung. 1983;33(4):587-590.

22. Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De Conno F. A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. Journal of Pain & Symptom Management. 1986;1(4):203-207.

23. Zeppetella G, Ribeiro Maria DC. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database of Systematic Reviews. 2006(1). http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004311/frame.html.

Ineligible Administration (6):

1. Beaver WT, Wallenstein SL, Houde RW, Rogers A. A comparison of the analgesic effects of pentazocine and morphine in patients with cancer. Clinical pharmacology and therapeutics. 1966(6):740-751. http://www.mrw.interscience.wiley.com/cochrane/clcentral/articles/061/CN-00296061/frame.html.

2. Bruera E, Belzile M, Neumann CM, Ford I, Harsanyi Z, Darke A. Twice-daily versus once-daily morphine sulphate controlled-release suppositories for the treatment of cancer pain. A randomized controlled trial. Support Care Cancer. Jul 1999;7(4):280-283.

3. Elsner F, Radbruch L, Loick G, Gartner J, Sabatowski R. Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain. J Palliat Med. Aug 2005;8(4):743-750.

4. Frankendal B, Kjellgren O. Severe pain in gynecologic cancer. Trial of pentazocine, morphine, and a placebo. Cancer. 1971(4):842-847. http://www.mrw.interscience.wiley.com/cochrane/clcentral/articles/687/CN-00005687/frame.html.

5. Osipova NA, Novikov GA, Beresnev VA, Loseva NA. ANALGESIC EFFECT OF TRAMADOL IN CANCER PATIENTS WITH CHRONIC PAIN A COMPARISON WITH PROLONGED-ACTION MORPHINE SULFATE. Current Therapeutic Research. 1991;50(6):812-821.


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6. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. Journal of Pain & Symptom Management. 2003;25(2):169-178.

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1. A randomized study to assess the efficacy and safety of fentanyl-TTS versus minor opioids in patients with moderate to severe chronic oncological pain previously treated with NSAIDs.: Janssen-Cilag, S.A.; Access Date: 20.06.2012 2007.

2. Apolone G, Corli O, Negri E, et al. Effects of transdermal buprenorphine on patients-reported outcomes in cancer patients: results from the Cancer Pain Outcome Research (CPOR) Study Group. Clin J Pain. Oct 2009;25(8):671-682.

3. Kerr RO, Tester WJ. Patient preference study comparing two extended-release morphine sulfate formulations (once daily Kadian versus twice daily MS Contin) for cancer pain. Clinical Drug Investigation (New Zealand). 2000;19(Jan):25-32.

4. Kress HG, Von der Laage D, Hoerauf KH, et al. A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain. J Pain Symptom Manage. Sep 2008;36(3):268-279.

5. Moertel CG, Ahmann DL, Taylor WF, Schwartau N. Comparative evaluation of marketed analgesic drugs. New England Journal of Medicine (USA). 1972;286(Apr 13):813-815.

6. Mystakidou K, Katsouda E, Kouloulias V, Kouvaris J, Tsiatas M, Vlahos L. Comparison of transdermal fentanyl with codeine/paracetamol, in combination with radiotherapy, for the management of metastatic bone pain. J Opioid Manag. Sep-Oct 2005;1(4):204-210.

7. Pistevou-Gompaki K, Kouloulias VE, Varveris C, et al. Radiotherapy plus either transdermal fentanyl or paracetamol and codeine for painful bone metastases: a randomised study of pain relief and quality of life. Curr Med Res Opin. 2004;20(2):159-163.

8. Tooley PJH, Cookson RF, Jones M, Nuyts GD. Medical events and resource utilisation in cancer-pain patients treated with strong opioids: an analysis of the UK General Practice Research Database. Journal of Drug Assessment. 2000;3(Part 3):221-234.

9. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev. 2007(4):CD003868.

Ineligible Outcome (9):

1. Bruera E, Belzile M, Pituskin E, et al. 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 Clin Oncol. Oct 1998;16(10):3222-3229.

2. Gabrail NY, Dvergsten C, Ahdieh H. Establishing the dosage equivalency of oxymorphone extended-release and oxycodone controlled release in patients with cancer pain: a randomized controlled study. Curr Med Res Opin. Jun 2004;20(6):911-918.

3. 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. Jun 1 1989;63(11 Suppl):2294-2297.

4. Guest JF, Ruiz FJ, Russ J, Gupta RD, Mihai A, Greener M. A comparison of the resources used in advanced cancer care between two different strong opioids: an analysis of naturalistic practice in the UK. Curr Med Res Opin. Feb 2005;21(2):271-280.

5. Hagen N, Thirlwell MP, Dhaliwal HS, Babul N, Harsanyi Z, Darke AC. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. J Clin Pharmacol. Jan 1995;35(1):37-44.


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6. Henriksen H, Knudsen J. MST Continuos tablets in pain of advanced cancer: A controlled study. Advances in Morphine Therapy. The 1983 International Symposium on Pain Control. 1984:123-126.

7. Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study. Clin Ther. Feb 2005;27(2):225-237.

8. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. Journal of Palliative Medicine. 2008;11(3):492-501.

9. Welsh J, Stuart JHB, Haveshaw T, Billiaert P, Caiman KC. A double blind cross-over study of two oral formulations of morphine. Cancer Chemotherapy and Selective Drug Development. 1984:153-158.

Ineligible Research Question (12):

1. Boureau F, Saudubray F, d'Arnoux C, et al. A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain. J Pain Symptom Manage. Oct 1992;7(7):393-399.

2. Gourlay GK, Cherry DA, Onley MM, et al. Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain. Pain. Feb 1997;69(3):295-302.

3. 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. Jan 2005;29(1):80-90.

4. Hasselstrom J, Alexander N, Bringel C, Svensson JO, Sawe J. Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients--a comparison of two oral formulations. Eur J Clin Pharmacol. 1991;40(6):585-591.

5. Kim DY, Song HS, Ahn JS, et al. The dosing frequency of sustained-release opioids and the prevalence of end-of-dose failure in cancer pain control: a Korean multicenter study. Support Care Cancer. Feb 2010;19(2):297-301.

6. Lorenz KA, Lynn J, Dy SM, et al. Evidence for improving palliative care at the end of life: A systematic review. Annals of Internal Medicine. 2008;148(2):147-159.

7. Maltoni M, Scarpi E, Modonesi C, et al. A validation study of the WHO analgesic ladder: a two-step vs three-step strategy. Support Care Cancer. Nov 2005;13(11):888-894.

8. Mercadante S, Caraceni A. Conversion ratios for opioid switching in the treatment of cancer pain: a systematic review. Palliative medicine. 2011;25(5):504-515.

9. Mercadante S, Fulfaro F, Casuccio A. Pattern of drug use by advanced cancer patients followed at home. Journal of Palliative Care. Spr 2001;17(1):37-40.

10. 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. Nov 1997;11(6):475-482.

11. 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. Apr 2010;39(4):712-720.

12. Sittl R, Nuijten M, Nautrup BP. Patterns of dosage changes with transdermal buprenorphine and transdermal fentanyl for the treatment of noncancer and cancer pain: a retrospective data analysis in Germany. Clin Ther. Aug 2006;28(8):1144-1154.


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Ineligible Language (8):

1. Bono AV, Cuffari S. [Effectiveness and tolerance of tramadol in cancer pain. A comparative study with respect to buprenorphine]. Drugs. 1997;53 Suppl 2:40-49.

2. Knudsen J, Mortensen SM, Eikard B, Henriksen H. Slow-release morphine tablets compared with conventional morphine tablets in the treatment of cancer pain. Ugeskrift for Laeger. 1985;147(9):780-784.

3. Li T-D, Ding, Yong W, Huang, Zhu H. Analgesic Effect of Lysinipinum, Codeine and Pethidine on Cancer Pain. Zhongguo Zhongliu Linchuang. 1995;22(1):39-42.

4. Ozturk T, Karadibak K, Catal D, Cakan A, Tugsavul F, Cirak K. [Comparison of TD-fentanyl with sustained-release morphine in the pain treatment of patients with lung cancer]. Agri. Jul 2008;20(3):20-25.

5. Qiu H, Wang J, Bao J. Clinical evaluation of durogesic in treatment of severe cancer pain. Zhongguo Zhongliu Linchuang. Jan. 20 2001;28(2):118-120.

6. Vaisman MA, Gantsev SK, Gazilov AA, Rudoi SV. [Comparative assessment of chronic pain syndrome treatment methods in patients with small pelvis neoplasms]. Anesteziol Reanimatol. Jul-Aug 1996(4):31-35.

7. Xu G, Duan L, Deng Y, et al. Post-market evaluation of fentanyl transdermal system on cancer pain. Zhongguo Zhongliu Linchuang. Apr. 20 2003;30(4):264-272.

8. Yao WX, Zhou H, Wang LY, Wei Y, Liu XY. [Efficacy comparison between morphine sulfate controlled-released tablet and morphine hydrochloride sustained-released tablet in treating cancer pain]. Ai Zheng. Dec 2007;26(12):1357-1359.

Full-text Not Available (10):

1. A comparative efficacy and tolerability study of palladone capsules and MST continus tablets in patients with cancer pain. Data on File. 2000.

2. De Conno F, Ripamonti C, Bianchi M, Gallucci M, Tamburini M, Ventafridda V. A CLINICAL COMPARISON BETWEEN ORAL MORPHINE AND METHADONE IN CANCER PAIN TREATMENT1986.

3. Goudas L, Carr DB, Bloch R, et al. Management of cancer pain. Volume 1. Volume 2: evidence tables (Structured abstract). Agency for Healthcare Research and Quality. 2001:196. http://www.mrw.interscience.wiley.com/cochrane/cldare/articles/DARE-12002008296/frame.html.

4. Houde RW. Clinical analgesic studies of hydromorphone. Advances in Pain Research and Therapy. 1986;8:129-135.

5. Kaiko RF, Savarese JJ, Goldenheim PD. CONTROLLED-RELEASED MORPHINE IN CHRONIC CANCER PAIN1986.

6. Moriarty M, McDonald CJ, Miller AJ. A randomised crossover comparison of controlled release hydromorphone tablets with controlled release morphine tablets in patients with cancer pain. Journal of Clinical Research. 1999;2(1-8):1-8.

7. Pan HJ, Zhou RY, Du M, Zhang RF, Lu YY. Comparative study of the analgesic effect of morphine sulfate and morphine HCl tablets in treatment of 84 patients with moderate to severe cancer pain. Chinese Journal of New Drugs. 2004;13(Jan):68-69.

8. Song H, Kim D, Ahn J, et al. The dosing frequency of sustained-release opioids and the prevalence of end-of-dose failure in cancer pain control: a Korean multicenter study. EJC Supplements. Sep 2009;7(2):184.


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9. Stambaugh JEJ, McAdams J. COMPARISON OF THE ANALGESIC EFFICACY AND SAFETY OF ORAL DOSES OF NALBUPHINE AND ACETAMINOPHEN ALONE AND IN COMBINATION TO PLACEBO IN PATIENTS WITH CHRONIC CANCER PAIN. Clinical pharmacology and therapeutics. 1985;37(2):231.

10. Xue P, Cai X, Wang LW. Analysis of therapeutic effects and pharmacoeconomics of oxycodone acetaminophen tablets and morphine sulfate controlled-release tablets in the treatment of advanced cancer pain. Vol 17:1967.

Published As Abstract Only (24):

1. Ahmedzai S, Brooks DJ. Transdermal fentanyl vs oral morphine in cancer pain. Journal of Palliative Care. Win 1995;11(4):62-62.

2. Babul N, Dhaliwal H, Sloan P, et al. Analgesic efficacy and safety of controlled release codeine and placebo in cancer pain. Clinical pharmacology and therapeutics. 1995;57(2):137.

3. Blokker MB. Methadone experience in opioid rotation for patients with cancer pain. Journal of Palliative Care. Fal 1999;15(3):61-61.

4. Brooks IM, Clark V, Blumenreich MS, Dejager RL. CONTINUOUS RELEASE MORPHINE SULFATE TABLETS IN CANCER PATIENTS WITH CHRONIC PAIN. Proceedings American Society of Clinical Oncology Annual Meeting. 1986;5:251.

5. Cherry DA, Gourlay GK, Cousins MJ. A COMPARATIVE STUDY OF THE EFFICACY AND PHARMACOKINETICS OF ORAL METHADONE AND MORPHINE IN THE TREATMENT OF CANCER PAIN. Pain. 1984(SUPPL. 2):S202.

6. Darke A, Moulin D, Provencher L, Laberge F, Harsanyi Z, Babul N. Efficacy, safety and pharmacokinetics of controlled release morphine suppositories and tablets in cancer pain. Clinical pharmacology and therapeutics. 1995;57(2):165.

7. Goldenheim PD, Savarese JJ, George E. MANAGEMENT OF LUNG-THORACIC CANCER PAIN WITH CONTROLLED-RELEASE MORPHINE SULFATE TABLETS. American Review of Respiratory Disease. 1987;135(4 PART 2):A243.

8. Hanks GW, Trueman T. CONTROLLED RELEASE MORPHINE TABLETS IN CHRONIC CANCER PAIN. Pain. 1984(SUPPL. 2):S406.

9. Holdsworth MT, Plezia PM, Davis A, Harinder RN, Garewal S, Clements W. AN EVALUATION OF SUSTAINED-RELEASE MORPHINE IN CHRONIC CANCER PAIN. Pharmacotherapy. 1989;9(3):178.

10. Kaiko R, Lacouture P, Hopf K. Analgesic onset and potency of oral controlled-release (CR) oxycodone and CR morphine. Clin Pharmacol Ther. 1996;59:130.

11. Khojasteh A, Evans W, Reynolds RD, Savarese J, Thomas G. SAFETY AND EFFICACY OF SLOW-RELEASE MORPHINE SULFATE TABLETS IN CANCER PAIN THERAPY. Proceedings American Society of Clinical Oncology Annual Meeting. 1986;5:256.

12. Krant M, Shepherd L. CANCER PAIN MANAGEMENT WITH CONTROLLED-RELEASE ORAL MORPHINE. Proceedings American Society of Clinical Oncology Annual Meeting. 1986;5:251.

13. Krawczeniuk MM, Davis LE, Abraham JL, et al. Controlled-release morphine (MS Contin) tablets vs fentanyl transdermal system (Duragesic) for the outpatient treatment of chronic cancer pain. Pharmacotherapy. 1996;16(3):500.

14. Leppert W. Assessment of analgesia, side effects and quality of life during cancer pain treatment with controlled release tramadol and dihydrocodeine - A prospective, randomized, cross-over trial. Psycho-Oncology. Sep 2007;16(9):S160-S161.


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15. Leppert W. Quality of life during cancer pain treatment with controlled release dihydrocodeine and tramadol. Psycho-Oncology. Jun 2008;17:S218-S218.

16. Levine MN, Sackett DL. CANCER PAIN HEROIN VS. MORPHINE. Clinical Research. 1985;33(2 PART 1):257A.

17. Meissner W, Schwittay A, Lux E, Kleeberg UR, Schneid H. A Pan-European Phase IV Open-label Multicentre Study in Patients With Breakthrough Cancer Pain (BTcP) Treated With Fentanyl Buccal Tablet (FBT) - Preliminary Data From Germany. European Journal of Cancer. Sep 2011;47(Suppl. 1):S226.

18. Sloan P, Dhaliwal H, Arkinstall W, et al. Evaluation of the efficacy and safety of controlled-released codeine and placebo in cancer pain. Anesthesia and analgesia. 1995;80(2 SUPPL.):S453.

19. Sunshine A, Olson N, Colon A, Rivera J, Fitzmartin R, Grandy R. Onset and duration of analgesia for controlled-release vs. immediate-release oxycodone alone and in combination with acetaminophen in postoperative pain. Clin Pharmacol Ther. 1995;57:137.

20. Tawfik M, Elborolossy K, Nasr F. TRAMADOL HYDROCHLORIDE IN THE RELIEF OF CANCER PAIN A DOUBLE BLIND COMPARISON AGAINST SUSTAINED RELEASE MORPHINE. Pain. 1990(SUPPL. 5):S377.

21. Ventafridda V, De Conno F, Tamburini M, Rocca E, Guarise G, Gallucci M. BUPRENORPHINE IN CANCER PAIN A CROSSOVER COMPARISON WITH PENTAZOCINE. Pain. 1984(SUPPL. 2):S408.

22. Ventafridda V, Saita L, Oliveri E, et al. A RANDOMIZED STUDY ON ORAL ADMINISTRATION OF MORPHINE SOLUTION AND SLOW RELEASE MORPHINE SULFATE TABLETS MST IN THE TREATMENT OF CANCER PAIN. Pain. 1987(SUPPL. 4):S157.

23. Walsh TD. CONTROLLED STUDY OF SLOW RELEASE MORPHINE FOR CHRONIC PAIN IN ADVANCED CANCER. Pain. 1984(SUPPL. 2):S202.

24. Watanabe S, Bruera E, Belzile M, Kuehn N, Hanson J. Capsules and suppositories of methadone for patients on high dose opioids for cancer pain. Clinical and Investigative Medicine. 1995;18(4 SUPPL.):B91.

Active Controlled Study (7):

1. 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 Clin Pharmacol. Jan 1998;38(1):74-81.

2. Brema F, Pastorino G, Martini MC, et al. Oral tramadol and buprenorphine in tumour pain. An Italian multicentre trial. Int J Clin Pharmacol Res. 1996;16(4-5):109-116.

3. Broomhead A, Kerr R, Tester W, et al. Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain. J Pain Symptom Manage. Aug 1997;14(2):63-73.

4. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. Jan 1 2004;22(1):185-192.

5. Deschamps M, Band PR, Hislop TG, Rusthoven J, Iscoe N, Warr D. The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine. J Pain Symptom Manage. Oct 1992;7(7):384-392.

6. 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. Pain. Jan 2003;101(1-2):193-198.

7. Mercadante S, Salvaggio L, Dardanoni G, Agnello A, Garofalo S. Dextropropoxyphene versus morphine in opioid-naive cancer patients with pain. J Pain Symptom Manage. Feb 1998;15(2):76-81.

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Opioid Therapy for Cancer-Related Pain - Donau-Universit¤t Krems

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