Supplementary table 1: Criteria for risk of bias ...10.1007/s00482-014-1452... · Supplementary...

Supplementary table 1: Criteria for risk of bias assessment for open-label

extension studies of RCTs (modifications to the Cochrane risk of bias tool are

marked in red)

1. Selection bias (modified). Selection bias (biased allocation to

interventions) due to inadequate generation of selecting patients for

open-label study

There is a low risk of selection bias if the investigators describe a random component

in the sequence generation process for inclusion into the open-label period such as:

referring to a random number table, using a computer random number generator,

coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots or

minimization (minimization may be implemented without a random element, and this

is considered to be equivalent to being random) or if all patients of the randomized

period are included into the open-label phase

There is a high risk of selection bias if the investigators describe a non-random

component in the generation process of the patients included into the open-label

phase such a location by judgment of the clinician or preference of the participant.

2. Allocation concealment (selection bias). Selection bias (biased allocation to

interventions) due to inadequate concealment of allocations prior to

assignment

There is a low risk of selection bias if the participants and investigators enrolling

participants could not foresee assignment because one of the following, or an

equivalent method, was used to conceal allocation: central allocation (including

telephone, web-based and pharmacy-controlled randomization); sequentially

numbered drug containers of identical appearance; or sequentially numbered,

opaque, sealed envelopes.

There is a high risk of bias if participants or investigators enrolling participants could

possibly foresee assignments and thus introduce selection bias, such as allocation

based on: using an open random allocation schedule (for example, a list of random

numbers); assignment envelopes were used without appropriate safeguards (for

example, if envelopes were unsealed or non-opaque or not sequentially numbered);

alternation or rotation; date of birth; case record number; or other explicitly

unconcealed procedures.

3. Blinding of participants and of personnel/care providers (performance bias).

Performance bias due to knowledge of the allocated interventions by

participants and by personnel/care providers during the study

There is a low risk of performance bias if blinding of participants was ensured and it

was unlikely that the blinding could have been broken; or if there was no blinding or

incomplete blinding, but the review authors judge that the outcome is not likely to be

influenced by lack of blinding.

There is a high risk of performance bias if blinding of participants was not ensured.

4. Blinding of outcome assessor (detection bias). Detection bias due to

knowledge of the allocated interventions by outcome assessors

There is low risk of systematic detection bias if the outcome assessor assessing

patient-reported outcomes is not the clinical investigator, but rather a statistician not

involved in the treatment of the patient. There is an unclear risk of systematic

detection bias if no details on the identity of the outcome assessor are reported.

There is a high risk of systematic detection bias if the outcome assessor was

involved in treatment of the patients.

5. Incomplete outcome data (attrition bias). Attrition bias due handling of

incomplete outcome data

There is low risk of bias if all randomized patients were reported or analyzed in the

group to which they were allocated by randomization and dropouts were analyzed by

baseline observation forward (BOCF) method. There is an unclear risk of bias if all

randomized patients were reported or analyzed in the group to which they were

allocated by randomization and dropouts were analyzed by last observation forward

method (LOCF). There is a high risk of bias if there was no intention-to-treat (ITT)

analysis and only completers were reported.

6. Selective reporting (reporting bias). Reporting bias due to selective outcome

reporting

There is low risk of reporting bias if the study protocol is available and all of the

study’s prespecified (primary and secondary) outcomes that are of interest in the

review have been reported in the prespecified way, or if the study protocol is not

available but it is clear that the published reports include all expected outcomes,

including those that were prespecified (convincing text of this nature may be

uncommon).

There is a high risk of reporting bias if not all of the study’s prespecified primary

outcomes have been reported; one or more primary outcomes is reported using

measurements, analysis methods or subsets of the data (e.g. subscales) that were

not prespecified; one or more reported primary outcomes were not prespecified

(unless clear justification for their reporting is provided, such as an unexpected

adverse effect); one or more outcomes of interest in the review are reported

incompletely so that they cannot be entered in a meta-analysis; the study report fails

to include results for a key outcome that would be expected to have been reported

for such a study.

7. Funding bias

We assumed a low risk of bias if the study was initiated by an investigator and the

study received no funding from a pharmaceutical company. We assumed a high risk

of bias if there was relationship between the authors and the pharmaceutical industry.

We extracted the following information on relationships with the pharmaceutical

industry: author affiliation with industry, funding of study by industry, industry

providing the study drug or statistical analysis performed by an industry-affiliated

statistician. In case of affirmative response to any of these questions, we concluded

that there was a funding bias.

Supplementary table 2: Characteristics of included studies

Caldwell 2002

Methods Disease: Osteoarthritis pain

Study setting: 16 sites in the US

Study duration: 26 weeks open-label extension

of a 4-week parallel randomized placebo-

controlled study

Participants Inclusion criteria: Patients had to be at least 40

years of age and have both a clinical diagnosis

and grade II-IV radiographic evidence of OA of

the hip and/or knee; have had prior suboptimal

analgesic response to treatment with NSAIDs

and acetaminophen or had previously received

intermittent opioid analgesic therapy; and have a

baseline visual analog scale (VAS) pain intensity

score of 40 mm in the index joint.

Exclusion criteria: Patients with serious

concomitant disease, chronic condition(s) that

might interfere with the assessment of pain and

other symptoms of OA, prior disease at the index

joint, surgery or the likelihood of requiring a

surgical procedure of the index joint(s) during the

trial; diseases other than OA not well managed

with treatment; weight 100 lbs; oral,

intramuscular, intravenous, intra-articular, or soft

tissue administration of steroids within 1 month of

study drug administration (two months, if at index

knee or hip joint); intra-articular

viscosupplementation (in the index joint) within

6 months of trial treatment; opioid therapy for

longer than 3 weeks prior to baseline; any history

of substance abuse within 2 years prior to

screening; and history of clinically significant

intolerance to opioids or any known

hypersensitivity to morphine or other opioid

analgesics.

Demographics of N= 181 patients in open-label

trial not reported; Demographics of patients of per

protocol analysis of randomized trial: mean age

62.6 years; 59% female; 86% white

Interventions Study medication: Extended release morphine

30 mg/d once daily in the morning or in the

evening oral

Rescue medication: Cardiovascular prophylactic

doses of aspirin (up to 325 mg/day) and

acetaminophen for non-OA symptomatology (up

to 2000 mg/day for a maximum of 3 consecutive

days). Acetaminophen had to be stopped 24

hours prior to efficacy assessments in RCT.

Allowed cotherapies: No information provided.

Outcomes Patients /included into open-label/ finishing

double-blind: 181/184

Patients finishing open-label/included into

open-label: 86/181

Patients finishing open-label/randomized at

study entry: 86/295

Patients dropping out due to lack of efficacy / included into open label: Not reported

Patients dropping out due to adverse events

during open label / included into open label:

60/181

Serious adverse events during open label /

included into open label: 4/181 (considered to be

associated with morphine); total SAE not

reported. No aberrant drug behavior reported

under SAE

Aberrant drug behavior: Not assessed

Deaths: Not explicitly stated

Pain intensity at the end of double-blind and

at end of open-label (ITT analysis): WOMAC

pain subscale*

Disability at the end of double-blind and at

end of open-label (ITT analysis): WOMAC

physical function subscale*

Changes of dosage during open-label:

Assessed**

Notes *Data of figure not suited for meta-analysis.

"Statistically significant reductions in pain

intensity and stiffness and improvements in

physical functioning from week 4 were observed

within the first week (week 5) of the open-label

extension trial and at all subsequent weeks.

Mean clinical improvements through week 12

corresponded with an increase in the mean daily

morphine dose. Subsequently (weeks 12 through

30), pain intensity, physical function, and stiffness

remained stable, which was consistent with a

stable average daily dose of morphine

approximately 50 mg/day) over this time period.

**"42 (49%) remained on the initial 30 mg/d

morphine dose; 7 patients increased their daily

dosage to 120 mg/d

Cloutier 2013

Methods Disease: Low back pain

Study setting: 6 sites in Canada

Study period: Not reported


of a 8 week cross-over randomized placebo-

controlled study

Participants Inclusion criteria: Adult patients (>18 years)

with low back pain of moderate or greater

intensity for the previous three months or longer

Exclusion criteria: Recently undergone or were

to commence any other treatment

(physiotherapy, corticosteroid injection, surgery);

required more than 12 tablets of 300/30 mg

acetaminophen/codeine; had pain that was

expected to be refractory to continuous opioid

therapy: had a significant source of pain other

than low back; elevated liver enzymes higher

than two times the upper limit or compromised

kidney function; corrected QT interval >450 msec;

known severe organ dysfunction; chronic

obstructive pulmonary diseases; peptic ulcer;

inflammatory bowel disease; psychological

dependence on narcotics; major psychiatric

disorders such as major depression; psychogenic

pain; involved in litigation that was related to pain

Total sample: (demographics of N=50 patients in

open-label trial not reported); Demographics of

patients of per protocol analysis; mean age 50.6

years; 50% female; 94.4% white

Interventions Study medication: Oxycodone/naloxone flexible

40/20 mg/d or 60/30 mg/d or 80/40 mg/d oral

Rescue medication: Acetaminophen(codeine

300/30 mg/ up to 6 times a day in RCT

Allowed cotherapies: Stable dosages of

antidepressants or anticonvulsants

Outcomes Patients included into open-label/finishing

double-blind: 50/54


open-label: 40/50


study entry: 40/83

Patients dropping out due to lack of efficacy during open label / included into open label: 2/50


during open label / included into open label: 3/50


included into open label: Not reported

Aberrant drug behavior during open label /

included into open label: Not assessed

Deaths during open label / included into open

label: Not explicitly stated


at end of open-label (ITT analysis): Pain NRS

0-4


end of open-label: Not assessed


Assessed*

Notes *The mean oxycodone dosage did not vary

greatly from the end of the double period (36/18

mg/d) to the end of the open-label (35.1/17.6

mg/d)".

Gordon 2010

Methods Disease: Low back pain




of one 8 weeks cross randomized placebo-

controlled study

Participants Inclusion criteria: Men and nonpregnant women

older than 18 years of age with low back pain of

at least moderate severity (2 on a five-point

ordinal scale) for more than six weeks duration

that was inadequately treated with nonopioids

were enrolled. Baseline assessments included an

evaluation of whether the pain represented a

neuropathic or nociceptive etiology.

Exclusion criteria: Patients whose analgesic

requirement was expected to exceed the

maximum BTDS dose, or who were refractory to

opioid therapy or had an allergy to

acetaminophen or opioids were excluded from

the study. Patients who were undergoing any

procedures or treatments (such as physiotherapy

or surgery) that were likely to affect their pain, or

those with a significant alternative source of pain,

were also excluded, as were patients who would

require the use of external heat sources. Other

exclusion criteria included elevated liver function

tests, severe organ dysfunction, head injury or

seizures, chronic obstructive pulmonary disease,

asthma, respiratory depression, cor pulmonale,

heart failure, peptic ulcer disease or

gastrointestinal tract inflammation. Patients with

suspected psychological dependence on narcotic

drugs or alcohol, or with a history of major

psychiatric disorders were also excluded.

Demographics of N=42 patients in open-label

trial not reported. Randomization sample: Mean

age 54,5 years; 47% female; race not reported

Interventions Study medication: Buprenorphine flexible 5 to

40 µg/d transdermal patch

Rescue medication: No information provided.



double-blind: 42/51


open-label: 26/42


study entry: 26/79

Patients dropping out due to lack of efficacy during open label / included into open label: Not reported


during open label / included into open label: Not

reported


included into open label: Not reported




label: Not reported


at end of open-label (no information provided,

if ITT analysis: Pain intensity NRS 0-10


end of open-label (not information provided if

ITT analysis): Quebec Back Pain Disability scale


Reported*

Notes *"Twenty-one patients completed six months of

open-label treatment at a final dose of 14.5±6.1

μg/h, compared with a mean final dose in the

double-blinded phase of 15.2±6.0 μg/h and a final

dose of 14.3±5.7 μg/h for all evaluable patients

who received open-label treatment."

Harati 2000

Methods Disease: Diabetic polyneuropathy pain




of a 6 week cross-over randomized placebo-

controlled study

Participants Inclusion criteria: At least moderate pain in

lower extremities for at least 3 previous months

Exclusion criteria: Contraindication against

tramadol; other reason for PNP; other pain

greater than PNP pain; severe depression;

creatinine clearance <=80 ml/min; clinically

significant medical condition: history of narcotic or

alcohol abuse; use of multiple dosages of

narcotics on a regular basis; evidence of

amputation, open ulcers, Charcot joint

Demographics: N=117; Mean age 58.4 years,

41.9% female, 91.4% white

Interventions Study medication: Tramadol flexible 100-400

mg/d oral

Rescue medication: Prohibited in RCT, unclear

if this was enforced in open-label


Anticonvulsants and antidepressants were

washed out.

Outcomes Patients included into open-label / finished

double blind: 117/131


open-label: 58/117


study entry: 58/131



during open label / included into open

label:13/117


included into open label: 10/117. No aberrant

drug behavior reported under SAE






at end of open-label (ITT analysis by LOCF of

former tramadol group): Pain relief NRS -1 to 4



Changes of dosage during open-label: Not

assessed

Johnson & Johnson 2010

Methods Disease: Low back and osteoarthritis pain

Study setting: > 100 sites in the US and Europe

Study period: 2007-2009


of 4 parallel randomized placebo-controlled

studies of 15 weeks each

Participants Inclusion criteria: Not reported

Exclusion criteria: Not reported

Demographics: Not reported

Interventions Study medication: Tapentadol flexible 100-500

mg/d

Rescue medication:

Paracetamol/acetaminophen 2 × 500 mg daily

was permitted during the study for a maximum of

7 consecutive days and no more than 14 days

out of 30 days.



double-blind: 1154/not reported


open-label : 698/1154


study entry: 698/not reported

Patients dropping out due to lack of efficacy during open label / included into open label:

Not reported



84/1154


included into open label: 139/1154. No Aberrant


Aberrant drug behavior: Not assessed


label: 3/1154


at end of open-label (ITT analysis): Pain relief

NRS 0-10*


end of open-label (ITT analysis): SF-36

physical functioning**


reported***

Notes *No SDs reported. "Pain intensity scores

remained stable or improved slightly over the

treatment period, with subjects who received

placebo in the parent study showing, on average,

the largest decrease in pain intensity scores

during tapentadol ER treatment in the current

OLE study. By Week 4 (month 1), mean pain

intensity scores in the Pla/Tap group were similar

to those in the other prior randomization groups.

Across all treated subjects, the mean baseline

pain intensity score was 3.87 and was 3.65 at the

end of the treatment period."

**No means and SDs reported. "Improvements

were observed over all SF-36 dimensions of

physical, social and mental wellbeing, as well as

for the physical and mental component summary

scores parameters."

***The mean total daily dose of tapentadol ER

was 368.2 mg."

Portenoy 2007

Methods Disease: Neuropathic, low back and osteoarthritis pain


Study period: 1998-2002

Study duration: 108 weeks open-label extension of 3 parallel randomized placebo-controlled studies of 12 weeks (2 studies) and 6 weeks (1 study) and two 12 weeks open-label studies

Participants Inclusion criteria: Adult patients (>=18 years of age) who had participated in 1 of 5 previous controlled clinical trials of oxycodone for noncancer pain (osteoarthritis pain, persistent back pain, or diabetic neuropathy pain) and who continued to require opioid analgesia for the relief of moderate to severe noncancer pain, were eligible for entry into this open-label registry study

Exclusion criteria: Patients who were unable to swallow tablets whole, who were undergoing chemotherapy or radiotherapy for cancer, who had a documented allergy to

oxycodone or other opioids, with self-reported past or present substance or alcohol abuse and those involved with litigation related to their pain and injury. and women who were pregnant or had the potential to become pregnant were excluded

Demographics: N=219; mean age 55.9 years; 57% female; 90% white

Interventions Study medication: Oxycodone flexible 20-140 mg/d

Rescue medication: Incomplete information provided*


Outcomes Patients included into open-label/finishing double-blind: 227/831

Patients finishing open-label/included into open-label : 39/227

Patients finishing open-label/randomized at study entry: 39/not reported

Patients dropping out due to lack of efficacy during open label / included into

open label: 17/227

Patients dropping out due to adverse events during open label / included into

open label: 41/227

Serious adverse events during open label / included into

open label: 9/227

Aberrant drug behavior during open label / included into

open label: Physician-investigators also completed a brief questionnaire at each visit indicating whether or not the patient showed any signs of problematic drug-related behavior. If the response was positive, the physician-investigators were further asked to indicate whether there was any indication of (1) an increased demand for drug despite a stable condition, (2) seeking medications from other practitioners, (3) repeated loss of scripts for CR oxycodone, or (4) any other behavior considered suspicious. An independent panel of experts evaluated potential abuse/misuse of CR oxycodone using the physician investigator assessments of drug-seeking behavior and the RADARS System

(Researched Abuse, Diversion, and Addiction-Related Surveillance System. Investigators: 13/219; Experts: 6/219

Deaths: 7/219**

Pain intensity at the end of double-blind and at end of open-label of patients on study medication (ITT analysis): Pain relief NRS 0-10***

Disability at the end of double-blind and at end of open-label of patients on study medication (ITT analysis): SF-36 physical functioning***

Changes of dosage during open-label: Reported****

Notes *Information on rescue analgesic use was not systematically collected, but a review of concomitant medication use on the basis of patient self-reports indicated that fewer than one-quarter of patients took another opioid analgesic at any time during the registry study.

**"a known interaction (phenylpropanolamine, oxycodone, and alcohol) in 1 case, a probable trauma in 1

case"

***No means or SDs reported

****Between the start of the study and the end of month 3, 44% of intent-to-treat patients showed an increase in their average total daily dose of CR oxycodone. This percentage dropped to 23% between month 4 and month 6, to 17% between month 10 and month 12, and remained at approximately 10% for each time interval thereafter through month 36 (range, 8% to 13%).

Richarz 2013

Methods Disease: Low back, musculoskeletal and

neuropathic pain

Study setting: 20 sites in Europe



of one open-label randomized study of 24 weeks

duration

Participants Inclusion criteria: Patients aged >= 18 years

with chronic noncancer pain (defined as pain

occurring 20 days/month for > 3 months) who

required continuous opioid therapy were enrolled.

Chronic pain conditions included low back,

musculoskeletal, and neuropathic pain and other

conditions. The study included opioid-naive

patients, patients receiving treatment with weak

opioids, patients taking <= 60 mg oral morphine

or an equivalent of another strong opioid, and

those patients using transdermal fentanyl 25

mcg/hour or transdermal buprenorphine 35

mcg/hour.

Exclusion criteria: Patients whose previous

hydromorphone or oxycodone therapy was

unsuccessful and patients with known

hypersensitivity to either drug were excluded.

Patients with a history of significant cardiac,

nervous system, or gastrointestinal conditions,

moderate-to severe hepatic impairment, severe

renal impairment, or hereditary problems of

galactose intolerance, Lapp lactase deficiency, or

glucose-galactose malabsorption were excluded.

Women who were pregnant or breastfeeding

were excluded.

Demographics (total sample):N=112; Mean age

58.1 years; 53.6% female; 100% white

Interventions Study medication: Hydromorphone flexible 8-32

mg/d oral vs. oxycodone flexible 20-80 mg/d oral

Rescue medication: Use of supplemental

analgesics (acetaminophen, up to 2 g/d) was

permitted but was not documented in patient

diaries



double blind: 112/277


open-label: 97/112


study entry: 97/504 (data from Binsfeld 2010)

Patients dropping out due to lack of efficacy during open label / included into open label: Not reported


during open label / included into open label: Not

reported/112


included into open label: 6/60 in hydromorphone

and 4/52 in oxycodone group. No aberrant drug

behavior reported under SAE




label: 0/112


at end of open-label: Change in pain severity

right now in brief pain inventory (data from

Binsfeld 2010)


end of open-label: Physical functioning SF-36:

Outcomes not reported


explicitly stated

Roth 2000


Study setting: Number of sites in US not

reported



with two optional 26 weeks extension trials

Participants Inclusion criteria: Persistent osteoarthritis pain

for at least one month and moderate or severe

pain intensity

Exclusion criteria: Severe organic dysfunction,

history of drug or alcohol abuse

Demographics: N=106; Mean age 32-88 years;

75.5% female; race not reported

Interventions Study medication: Oxycodone flexible 20-80

mg/d oral

Rescue medication: NSAIDs permitted


Outcomes Patients included into open-label/randomized

at study entry: 106/133


open-label: 58/106 after 6 months, 41/106 after

12 months and 15/106 after 18 months

Patients finishing open-label at 18

months/randomized at study entry: 15/133

Patients dropping out due to lack of efficacy




32/106


included into open label: 13/106 patients

hospitalized. One potential aberrant drug

behavior reported under SAE*






at end of open-label (No ITT analysis):

Reported **




Reported***

Notes *Confusion and disorientation while receiving

"many CNS-active medications"

**Data extracted from figure; mean value of

means of oxycodone 20 and 40 mg/d calculated

(mean 2.0, SD 1.5)

***The dose of oxycodone became constant at

approximately 40 mg/d by week 16.

Sandner-Kiesling 2010

Methods Diseases: Low back and osteoarthritis pain

Study setting: > 50 sites in Europe



of two 12- weeks parallel randomized placebo-

controlled studies

Participants Inclusion criteria:

Males and females 18 years of age if they had a

documented history of moderate- to-severe

noncancer pain that required continued around-

the-clock opioid therapy (oxycodone equivalent

of 20 mg/day and 50 mg/day)Exclusion criteria:

Any history of hypersensitivity to oxycodone,

naloxone, or related products; patients with

cancer pain, rheumatoid arthritis, evidence of

clinically unstable disease, or evidence of

impaired liver/kidney function upon entry.

Demographics: Mean age: 56.2 years; 61%

female; race not reported

Interventions Oxycodone/naloxone: Up to 80/40 mg/d

Rescue medication: "After this period

investigators could prescribe also other analgesic

rescue medicine, if needed."



double-blind: 258/296


open-label: 234/258


study entry: 234/463




24/379


included into open label: 88/379. No aberrant







at end of open-label (ITT analysis): Pain NRS

0-10


end of open-label (ITT analysis): Brief Pain

Inventory Interference Scale 0-70


Assessed*

Notes *"The mean total daily dose of oxycodone (±SD)

increased slightly from 35.6 ± 16.53 mg after 2

weeks to 43.7 ± 22.53 mg at the end of the

extension phase,"

Thorne 2008




Study duration: 26 weeks open-label extension of a 8

week cross-over randomized placebo-controlled study

Participants Inclusion criteria: Men and nonpregnant, non-

nursing women over the age of 18 years, diagnosed

with OA and requiring the use of acetaminophen, anti-

inflammatory agents or combination opioid and

nonopioid analgesics for at least three months were

eligible for the present study. OA was defined by the

presence of hip and/or knee symptoms (pain,

stiffness, disability) and signs (bony crepitus), as well

as radiographic evidence of OA in the medial and/or

lateral tibiofemoral compartment (with or without

patellofemoral OA), or in the hip. Radiographic

evidence was defined by the presence of at least one

of the following: osteophytes, joint space narrowing,

periarticular sclerosis or subchondral cysts, with a

minimum grade 2 severity, as illustrated in the Atlas of

Standard Radiographs of Arthritis. Patients with more

advanced grades were eligible if they were not

awaiting surgery. Patients using only acetaminophen

at the time of enrollment were required to have pain of

at least moderate intensity (a 2 or greater on a 0 to 4

ordinal pain scale) at both visits 1 and 2. Patients

treated with any other opioid or nonopioid analgesic

were required to have at least moderate pain (a 2 or

greater on a 0 to 4 ordinal pain scale) after a two to

seven day washout period at visit 2.

Exclusion criteria: Patients who required more than

eight tablets per day of acetaminophen plus codeine,

or its analgesic equivalent, or with a history of drug or

alcohol abuse were also excluded. The following

medical conditions were exclusionary: any other form

of joint disease or previous replacement of the study

joint, renal or hepatic impairment (alanine

aminotransferase or aspartate aminotransferase more

than two times the upper limit of the normal range),

shortened gastrointestinal transit time, peptic ulcer

disease, inflammatory disease of the gastrointestinal

tract, cardiac or respiratory conditions that put the

patient at risk for respiratory depression, a history of

seizures or a recognized risk for seizure, and any

other condition that would adversely affect the

patient’s safety or obscure the assessment of efficacy.

Patients receiving monoamine oxidase inhibitors,

carbamazepine, quinidine, selective serotonin

reuptake inhibitors or tricyclic antidepressants,

cyclobenzaprine, promethazine, neuroleptics, warfarin

or digoxin were excluded. Patients who received an

investigational drug within the last month were also

ineligible.

Demographics of N=53 patients in open-label trial not

reported. Randomization sample: Mean age 61 years,

55% female, race not reported

Interventions Study medication: Tramadol flexible 100-400 mg/d

oral

Rescue medication: No rescue medication allowed


Outcomes Patients included into open-label/finishing double-

blind: 53/100

Patients finishing open-label/included into open-

label: 29/53

Patients finishing open-label/randomized at study

entry: 29/100




Serious adverse events during open label / included

into open label: 2/53. No aberrant drug behavior

reported under SAE

Aberrant drug behavior during open label / included

into open label: Not assessed

Deaths during open label / included into open label:

Not explicitly stated

Pain intensity at the end of double-blind and at

end of open-label (no information provided if ITT

analysis was conducted): Pain relief VAS 0-100 *

Disability at the end of double-blind and at end of

open-label (no information provided if ITT analysis

was conducted): SF-36 physical component score *

Changes of dosage during open-label: Assessed**

Notes *Open-label average, but not end of open-label values

reported

**"The mean final dose of CR tramadol was

313.2±100.1 mg/day, compared with 330.2±93.7

mg/day during the last week of double-blind active

treatment for these patients."

Supplementary table 3: Assessment of risks of bias in included studies

Caldwell 2002

Bias Authors'

judgment Support for judgment

Selection bias High risk

Not all patients randomized

period included into open-

label phase. Criteria for

selecting patients for open-

label study not detailed

Allocation concealment (selection

bias)

High risk Open-label

Blinding of participants and

personnel (performance bias) Open-label

Blinding of outcome assessment

(detection bias)


Incomplete outcome data (attrition

bias)

Unclear risk

ITT analysis, method not

reported

Selective reporting (reporting bias) High risk

No prespecified outcomes for

open-label phase reported

Confounding bias High risk

Acetaminophen for non-OA

symptomatology (up to 2000

mg/day for a maximum of 3

consecutive days.

Acetaminophen had to be

stopped 24 hours prior to

efficacy assessments in RCT.

No details on open-label

period reported

Funding bias High risk

Study funded by

manufacturer of the drug

Cloutier 2003

Bias Authors'


Selection bias High risk Not all patients randomized

period included into open-label

phase. Criteria for selecting

patients for open-label study not

detailed


bias)



personnel (performance bias)



(detection bias)



bias)

Unclear risk ITT analysis, method not

reported

Selective reporting (reporting bias) High risk No prespecified outcomes for


Confounding bias High risk Acetaminophen(codeine 300/30

mg/ up to 6 times a day in RCT

Funding bias High risk Study funded by manufacturer

of the drug

Gordon 2010

Bias Authors'






detailed


bias)






(detection bias)



bias)

Unclear risk No details reported if ITT

analysis

Selective reporting (reporting bias) High risk No prespecified outcomes for

open-label phase reported; SAE

not reported

Confounding bias Unclear risk No information provided


of the drug

Harati 2000

Bias Authors'






detailed


bias)






(detection bias)



bias)

Unclear risk ITT by LOCF

Selective reporting (reporting bias) Low risk Prespecified outcomes for open-

label phase reported

Confounding bias Unclear risk Rescue medication prohibited in

RCT, unclear if this was

enforced in open-label


of the drug

Johnson &Johnson 2010

Bias Authors'


Selection bias Unclear risk Not all patients randomized




detailed


bias)






(detection bias)



bias)

Unclear risk ITT analysis by LOCF

Selective reporting (reporting bias) Low risk All prespecified outcomes for


Confounding bias High risk Paracetamol/acetaminophen 2

× 500 mg daily was permitted

during the study for a maximum

of 7 consecutive days and no

more than 14 days out of 30

days


of the drug

Portenoy 2007

Bias Authors'






detailed


bias)






(detection bias)



bias)


reported



Confounding bias Unclear risk No details on rescue medication

reported


of the drug

Richarz 2013

Bias Authors'






detailed


bias)






(detection bias)



bias)

Unclear risk ITT analysis by LOCF



Confounding bias High risk Use of supplemental analgesics

(acetaminophen, up to 2 g/d)

was permitted but was not

documented in patient diaries


of the drug

Roth 2000

Bias Authors'






detailed


bias)






(detection bias)



bias)

High risk No ITT analysis

Selective reporting (reporting bias) High risk Prespecified outcomes for open-

label phase not reported

Confounding bias High risk Rescue medication allowed and

not controlled for


of the drug

Sandner-Kiesling 2010

Bias Authors'






detailed


bias)






(detection bias)



bias)


reported



Confounding bias High risk Rescue medication allowed and

not controlled for


of the drug

Thorne 2008

Bias Authors'






detailed


bias)






(detection bias)



bias)

High risk No information provided if ITT

analysis

Selective reporting (reporting bias) High risk Prespecified outcomes for open-

label phase not reported

Confounding bias High risk All analgesics besides

acetaminophen prohibited


of the drug

Supplementary table 1: Criteria for risk of bias ...10.1007/s00482-014-1452... · Supplementary...

Documents

Transcript of Supplementary table 1: Criteria for risk of bias ...10.1007/s00482-014-1452... · Supplementary...