McMaster University

Michael G. DeGroote
National Pain Centre

Scope of Search

Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain

Appendix B-13: Meta-analysis Evidence Table

  • Placebo-
    controlled
    (Neuropathic
    pain)
  • Placebo-
    controlled
    (Nociceptive
    pain)
  • Placebo-
    controlled
    (Fibromyalgia
    pain)
  • Placebo-
    controlled
    (Mixed pain)
     
  • Opioids
    versus
    other analgesics
     
  • N of 1
    randomized
    trial
     

1. Placebo-controlled (Neuropathic pain)

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Harati
1998
USA
Parallel

Quality: 4

Diabetic neuropathy

131 (49)

Tramadol
50 – 400 mg/d for 6 wk

Primary: Pain intensity* (5-point Likert scale).

Secondary: Pain relief, quality of life (Medical Outcomes Study): physical functioning*, social functioning, current health perception, psychological distress, overall role functioning, and the two overall sleep problem indexes and sleep subscales.

Tramadol, at an average dose of 210 mg/d was significantly more effective than placebo. Patients on tramadol scored significantly better in physical and social functioning.

Sindrup
1999
Germany Crossover

Quality:4

Polyneuropathy

45 (11)

Tramadol
200 – 400 mg/d for 4 wk

Primary: Pain ratings* (0-10 NRS), paraesthesia and touch-evoked pain.

Secondary: Dynamic allodynia, rescue medication, patient’s preference.

Pain, paraesthesia, touch-evoked pain and allodynia were lower on tramadol than on placebo. NNT to obtain one patient with ≥50% pain relief was 4.3 (95% CI 2.4 to 20).

Boureau 2003
France

Parallel

Quality:5

Postherpetic neuralgia

127 (19)

Tramadol
100 – 400 mg/d for 6 wk

Primary: Pain intensity (100-mm VAS* and 5-point NRS).

Secondary: Global improvement, quality of life (Nottingham scale) and rescue medication (paracetamol).

Mean pain intensity was significantly lower with tramadol in both per protocol and intention-to-treat population. No significant difference was found between groups in pain intensity on a 5-point verbal scale or in quality of life measurement.
Norrbrink
2009

Sweden
Parallel Quality:3
Spinal Cord Injury with neuropathic pain at or below level > 6 months. 35 (13)

Tramadol
50 mg TID – 400 mg/day.

For 4 weeks.

Primary: present, general and worst pain. MPI subscale pain severity.

Patient Global Impression of Change.

Secondary: anxiety, global life satisfaction, and sleep quality.

Significant differences in present pain, general pain, and worst pain as well as MPI favouring tramadol. Seven patients on active drug (30%) rated an improvement, but only 4 (17%) rated their pain to be much improved. One patient in the placebo group reported minimal improvement (8%). No patients in either group reported their pain to be very much improved.

Watson and Babul
1998

Canada
Crossover

Quality:3

Postherpetic neuralgia

50 (12)

CR Oxycodone 20 – 60 (mean 45) mg/d for 4 wk

Primary:  Pain intensity (100-mm VAS* and 5-point categorical scale).

Secondary:  Pain relief, steady pain, brief pain, skin pain, disability* (using a categorical scale: 0= no disability, 3= severe disability), BDI, POMS.

Oxycodone was significantly better in pain relief, reductions in steady pain, allodynia, paroxysmal spontaneous pain, global effectiveness, disability and masked preference.

Watson
2003

Canada
Crossover

Quality:4

Diabetic neuropathy

45 (3)

CR Oxycodone 20 – 80 (mean 40) mg/d for 4 wk

Primary:  Pain intensity (100-mm VAS* and 5-point categorical scale).

Secondary: Pain relief, steady pain, brief pain, skin pain, PDI*, SF-36 health survey, pain and sleep questionnaires.

Oxycodone was significantly better on daily pain, steady pain, brief pain, skin pain,total pain and disability. NNT to obtain one patient with at least 50% pain relief was 2.6

Gimbel
2003
USA
Parallel

Quality:5

Diabetic neuropathy

159 (44)

CR Oxycodone 20 – 120 (mean 37) mg/d for 6 wk

Primary:  Pain intensity* (0-10 numeric scale).

Secondary: Current and worse pain, satisfaction, BPI* (physical function score), SF-36 health survey.

Oxycodone provided more analgesia than placebo in the intent-to-treat cohort.

Huse
2001
Germany Crossover

Quality:1

Phantom limb pain

12 (3)

SR morphine 70 – 300 (mean 120) mg/d for 4 wk

Primary:  Pain intensity* (2-cm VAS)

Secondary: PES, SDS, PRSS, WHYMPI, BSS.

Based on pain diary data, 42% of patients on morphine showed a pain reduction of more than 50% compared to only one patient in the placebo group.

Harke
2001
Germany Parallel

Quality:4

Peripheral neuropathy

38 (3)

SR morphine 90 mg/d for 1 wk Pain intensity* (0-10 numeric analogue scale), and reactivation of their spinal cord stimulator. The differences between morphine and placebo were not significant.

Wu 2008
USA
Crossover

Quality:4

Postamputation pain

60 (25)

SR Morphine 15 - 180 mg day x 6 weeks.

Primary: Average change in overall pain intensity from the baseline to the last week of maintenance therapy using 0-10.

Secondary: Pain relief (0-100%) and the interference and general activity subscales from the MPI. Side effects.

Morphine provided lower pain scores compared with placebo. The mean percent pain relief during treatment with placebo and morphine was 19 53%, respectively. NNT to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively.

Raja 2002(a)USA
Crossover

Quality:4

Postherpetic neuralgia

76 (32)

CR morphine 15-240 (mean 91) mg/d for 6 wk or methadone 15mg/d.

Primary: Pain intensity* (0-10 NRS).

Secondary: Pain relief, cognitive function, MPI* (physical functioning subscale), sleep, mood, global preference.

Morphine reduced pain (1.9) more than placebo (0.2). Pain relief was greater with morphine (38%) compared with placebo (11%).

Gilron
2005
Canada
Crossover

Quality:4

35 diabetic neuropathy and 22 postherpetic neuralgia.

57 (16)

A) SR morphine maximum tolerated for 5 wk.

B) SR morphine maximum tolerated combined with gabapentin for 5 wk

C) Gabapentin maximum tolerated for 5 wk

Primary: Pain intensity* (0-10 NRS)

Secondary: SF-MPQ, Maximal tolerated doses, Mood (BDI), SF-36 (physical function*), Mental Status (Mini-Mental), and global pain relief.

Mean pain intensity at the maximal tolerated dose was 4.49 with placebo, 4.15 with gabapentin, 3.7 with morphine and 3.06 with gabapentin-morphine combination. Total scores in SF-36 were lower with gabapentin-morphine combination than placebo or each drug alone.

Khoromi 2007
USA
Crossover

Quality:1

Chronic lumbar radiculopathy (sciatica)

55 (27)

A) SR morphine 15-90 mg/d

B) Nortriptyline 25-100 mg/d

C) Combination

Each phase: 5 + 2 + 2 wk

Primary: Average leg pain during the two weeks*.

Secondary: Global pain relief, ODI*, BDI and SF-36.

None of the treatments produced significant reductions in average leg pain or other leg or back pain scores.

Simpson 2007
USA
Crossover (Enrichment)

Quality:4

Acute on chronic pain

79 (4)

Fentanyl buccal tablet 100-800 mcg. (This formulation is not available in Canada)

Duration: 9 episodes or 21 days

Primary: Sum of pain intensity differences (0-10 NRS) in the first 60 minutes (SPID-60).

Secondary: Proportion of breakthrough episodes with 33% and 50% improvement; time to significant pain relief, pain intensity differences, proportion of episodes with meaningful pain relief, and proportion of episodes that required supplemental medication.

SPID-60 was significantly greater for breakthrough pain episodes treated with fentanyl buccal tablets compared with those in which placebo was administered.

2. Placebo-controlled (Nociceptive pain)

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Roth 1998
USA
Parallel
(Enrichment)

Quality:3

Osteoarthritis (not specified)

42 (8)

Tramadol 200 – 400 mg/d for 2 wk

Primary: Time to exit from the study due to therapeutic failure.

Secondary: Severity of pain*(0-3 numeric scale), Ability to perform activities.

Time to exit from the study because of insufficient pain relief was longer in the tramadol group. Pain at rest and severity of pain on motion were less in the tramadol group. No differences were noted in general severity of current pain and on disability to perform ADLs.

Silverfield
2002

USA
Parallel

Quality:5

Osteoarthritis (not specified)

308 (68)

Tramadol 37.5 – 70 mg/d + acetaminophen 325 – 650 mg/d for 1.5 wk

Primary: Pain intensity*(0-3 numeric scale), Pain relief.

Secondary: SPID, WOMAC* (physical function subscale).

The addition of tramadol/acetaminophen to NSAID or COX-2 selective inhibitor therapy was effective in the treatment of OA flare pain.

Emkey
2004
USA
Parallel

Quality:3

Osteoarthritis (not specified)

307 (80)

Tramadol 37.5 – 300 mg/d + acetaminophen 325 – 2600 mg/d for 13  wk

Primary:  Pain intensity* (100-mm VAS)

Secondary: Pain relief, WOMAC* (physical function subscale), SF-36 survey.

Mean final VAS scores, mean final pain relief rating scores, WOMAC physical function and SF-36 role-physical measures were all significantly better with tramadol/acetaminophen than with placebo.

Fleischmann
2001
USA
Parallel

Quality:4

Osteoarthritis knee

129 (93)

Tramadol 50-400 mg/d for 12 wk

Primary:  Pain intensity* (0-4 Likert scale).

Secondary: Pain relief, WOMAC* (overall), global assessment, time to failure

Mean final pain intensity score, and all secondary outcomes were significantly better in the tramadol group than in the placebo group.

Babul
2004

USA

Parallel

Quality:4

Osteoarthritis knee

246 (122)

CR Tramadol 100 – 400 mg/d for 11 wk

Primary: Pain intensity* (100-mm VAS). 

Secondary: WOMAC* (physical function subscale), CSPI.

Tramadol resulted in significant improvements in pain, stiffness, physical function, global status and sleep.

Ruoff
1999
USA
Parallel

Quality:5

Chronic joint pain

465 (113)

A) Tramadol starting at 200mg/d

B) Tramadol starting at 50mg/d and reaching 200 mg/d on day 4

C) Tramadol starting at 50mg/d and reaching 200 mg/d on day 10

Duration of treatment: 2 wk

Primary: Discontinuation due to adverse effect or ineffectiveness. 40 patients (30.8% of group taking 200 mg/d from day 1) reached the primary end point; 31 patients (24.0% from day 4); 20 patients (15.2% from day 10); and 3 (4.4% of placebo group).

Schnitzer
1999
USA

Parallel
(Enrichment)

Quality:3

Osteoarthritis knee

240 (4)

Tramadol 200 mg/d + Naproxen 750 mg/d reduced by 250 mg/d every 2 wk.

Duration total: 8 wk

Primary: Minimum effective naproxen dose. The addition of tramadol allowed a significant reduction in the dosage of naproxen without compromising pain relief.

Schnitzer
2000
USA

Parallel

(Enrichment)

Quality:5

Low-back pain

254 (22)

Tramadol 200 – 400  (mean 242) mg/d for 4 wk

Primary:  Time to exit the double-blind trial.

Secondary: Pain intensity* (10-cm VAS), Pain relief, SF-MPQ, RDQ*

Discontinuation rate due to therapeutic failure was 20.7% in the tramadol group and 51.3% in the placebo group. Pain scores, MPQ and RDQ were significantly better in the tramadol group.

Ruoff
2003

USA

Parallel

Quality:3

Low-back pain.

322 (157)

Tramadol 37.5 – 300 (mean 157.5) mg/d + acetaminophen 325 – 2600 mg/d for 13 wk

Primary: Pain intensity* (100-mm VAS)

Secondary: PRRS, SF-MPQ, RDQ*, SF-36.

Pain intensity, final PRRS scores, RDQ scores and many subscales of SF-MPQ and SF-36 were significantly better with tramadol than with placebo.

Peloso
2004

Canada
Parallel

Quality:3

Low-back pain

338 (191)

Tramadol 37.5 – 300 (mean 158) mg/d + acetaminophen 325 – 2600 mg/d for 91 days

Primary:  Pain intensity* (100-mm VAS)

Secondary: PRRS, SF-MPQ, SF-36, RDQ*, overall medication assessment.

VAS, pain relief scores, RDQ, physical-related subcategories of MPQ and Sf-36 were significantly better for tramadol/acetaminophen than for placebo. More patients rated tramadol/acetaminophen as “very good” or “good” than placebo.

Vorsanger
2008

USA and
CANADA

Parallel
(Enrichment)

Quality:4

Chronic Low Back Pain

386 (145)

A) CR Tramadol 300 mg/d* for 12 wk

B) CR Tramadol 200 mg/d for 12 wk

Primary: pain intensity VAS since the previous visit.

Secondary: current pain intensity VAS*, global assessment of study medication, Roland Disability Index*, and overall quality of sleep.

The placebo group had greater mean deterioration for pain intensity since the previous visit (+12.2 mm) compared with patients who continued to receive tramadol 300 mg (+5.2 mm) and patients whose dose was reduced to Tramadol 200 mg (+7.8). There were better response in the tramadol groups versus placebo for the secondary variables.

Burch 2007
Canada
Parallel
(Enrichment)

Quality:5

Osteoarthritis knee

646 (155)

Tramadol (200-300 mg/d) for 12 wk

Primary: Pain intensity (11-point NRS)*

Secondary: Patient and physician global impression of change.

The absolute mean reduction in pain intensity in the tramadol group was 3.0 ± 2.1. There was a statistically significant difference from placebo.

Kosinski
2007

Gana 2006
Schein 2008USA
Parallel

Quality:2

Osteoarthritis (knee or hip), ACR Functional Class I-III

1020 (462)

A) Tramadol ER 100 mg/d for 12 wk

B) Tramadol ER 200 mg/d for 12 wk

C) Tramadol ER 300 mg/d for 12 wk

D) Tramadol ER 400 mg/d for 12 wk

Primary: Pain intensity (100-mm VAS)*

Secondary: Chronic pain sleep inventory.

Mean pain reduction at 12 weeks was -0.4 mm and -21.5 mm for tramadol ER and placebo, respectively (P < 0.001).

Lee
2006

Korea

Parallel

Quality:3

Rheumatoid arthritis pain inadequately controlled by NSAIDs and DMARD

277 (10)

Tramadol
37.5 mg/d plus acetaminophen 325 mg/d for 1 wk

Primary: mean daily pain relief score on a 6-point scale.

Secondary:  mean daily pain intensity (100-mm VAS)*, pain intensity at day 7, subjects and investigators mean overall assessment, physical function* (Health Assessment Questionnaire).

Pain relief scores and Pain intensity scores were significantly better in the tramadol/acetaminophen group compared with the placebo group Physical function did not differ significantly between tramadol/acetaminophen and placebo.

Thorne
2008

Canada
Crossover

Quality:3

OA knee or hip

100 (25)

CR Tramadol: 150 – 300 mg x 8 weeks

Primary: daily diary pain intensity score*

Secondary: WOMAC pain and physical function*

Tramadol resulted in significantly lower pain intensity (37.4±23.9) compared with placebo (45.1±24.3). WOMAC index subscale score for pain and physical function were significantly better with tramadol than placebo.

Boureau
1991

France
Parallel

Quality:3

Rheumatoid Arthritis

40 (2)

Codeine 90 mg/d + acetaminophen 1500 mg/d for 1 week

Primary:  Pain intensity (100-mm VAS* and 5-point Likert scale).

Secondary: Pain relief, activity, sleep, overall efficacy.

Analgesic efficacy was significantly better with codeine/acetaminophen than with placebo for all criteria except the number of awakenings.

Arkinstall
1995
Canada
Crossover

Quality:3

Mixed nociceptive

46 (16)

CR Codeine
200 – 400 mg/d for 1 week

Primary: Pain intensity (100-mm VAS* and 5-point categorical scale).

Secondary: Rescue acetaminophen + codeine consumption, PDI*, and patients’ and investigators’ treatment preferences.

The codeine group was significantly better on overall pain intensity (35±18) than placebo (49±16), on categorical pain intensity and on pain scores by day and time of day. Daily rescue analgesic consumption was lower in the codeine group. Disability was lower in the codeine group compared with placebo.

Peloso
2000
Canada
Parallel

Quality:3

Osteoarthritis hip or knee

103 (37)

CR Codeine 100 – 400 mg/d for 4 wk

Primary: WOMAC – Pain intensity* (0-500 VAS).

Secondary:  WOMAC* (stiffness and physical function), sleep, global assessment.

All variables in the efficacy analysis indicated superiority of codeine over placebo. The WOMAC improved 44.8% over baseline in the codeine group compared with 12.3% in the placebo group.

Roth
2000
USA
Parallel

Quality:3

Osteoarthritis

133 (70)

A) CR Oxycodone 20mg/d for 2 wk(*)

B) CR Oxycodone 40mg/d for 2 wk

Primary: Pain intensity* (4-point numeric scale).

Secondary: Quality of sleep, BPI, Interference of pain on key functional activities.

Oxycodone was superior to placebo in reducing pain intensity and the interference of pain with mood, sleep and enjoyment of life.

Caldwell
1999
USA
Parallel
(Enrichment)

Quality:3

Osteoarthritis

107 (36)

A) IR Oxycodone 20 mg/d + acetaminophen 1300 mg/d for 4 wk(*)

B) CR Oxycodone 20 mg/d for 4 wk

Primary: Pain intensity* (4-point numerical scale).

Secondary: Global measure of sleep.

Pain intensity and quality of sleep were significantly improved in both active groups compared with the placebo group.

Webster
2006

USA
Parallel

Quality:3

Low-back pain

719 (391)

A) Oxycodone 10-80 mg/d once daily*

B) Oxycodone 10-80 mg/d + ultra-low dose naltrexone once daily

C) Oxycodone 10-80 mg/d + ultra-low dose naltrexone twice daily

Duration: 12 wk

Primary: 11-point numerical diary pain intensity scale*

Secondary: SF-12, ODI*, Quality of analgesia, global assessment of study drug.

All active treatment groups were significantly better than placebo on measures of pain reduction, physical component score of the SF-12 and ODI.

Markenson
2005

USA
Parallel

Quality:4

Osteoarthritis

109 (73)

Oxycodone CR 10-120 (mean 57) mg/d for 12 wk

Primary: BPI average pain intensity*, WOMAC scores at days 30 and 60, the number of patients who discontinued the study due to inadequate pain control.

Secondary: BPI (pain interference and function), WOMAC, PGI, time to stable dosing, percentage of patients achieving stable dosing within 30 days, average daily dose at completion of initial titration, patient satisfaction, average and current pain intensity from pain diaries.

Oxycodone was significantly superior to placebo in decreasing average pain intensity and in reducing pain induced interference with general activity, walking ability (except at day 30), and normal work, as well as mood, sleep, relations with people (at days 60 and 90), and enjoyment in life. Daily functioning, as measured by WOMAC was also significantly improved in the oxycodone group. In the placebo group, a significantly greater percentage of patients discontinued due to inadequate pain control.

Chindalore
2005

USA
Parallel

Quality:3

Osteoarthritis hip and knee

362 (121)

A) Oxycodone 10 mg qid*

B) Oxycodone 10 mg plus ultra-low dose naltrexone 0.001 mg qid

C) Oxycodone 20 mg plus ultra-low dose naltrexone 0.001 mg bid

Duration: 3 wk

Primary: Pain intensity measured by 11-point NRS*

Secondary: quality of analgesia, pain control, global assessment of study drug, SF-12, WOMAC.

Although oxycodone was significantly better than placebo at wk 1, this treatment was not different from placebo at later time points. Oxycodone was significantly better than placebo on the pain subscale, the physical function scale, and the WOMAC total score, but at week 1 only.

Ma
2008
China

Parallel

Quality:4

Chronic neck pain with acute flare ups

116 (0 on day 7)

A) CR Oxycodone 5 to 10 mg bid for 4 wk Primary and secondary: Frequency of pain episodes, pain intensity* (VAS), quality of life (QOL)*, quality of sleep (QOS), side effects, withdrawal symptoms, SF-36, performance status, patient satisfaction. Results were extracted for the 7-day measurement. The frequency of pain episodes and VAS were decreased significantly with Oxycodone. Improvements in QOL and QOS were significant on day 3 after treatment with Oxycodone. Most domains of SF-36 were improved in the treated patients at the end of study.

Caldwell
2002

USA
Parallel

Quality:3

Osteoarthritis hip and/or knee

295 (111)

A) ER Morphine 30 mg/d (morning) for 4 wk*

B) ER morphine 30 mg/d (evening) for 4 wk

C) CR morphine 15 mg twice a day for 4 wk

Primary: WOMAC OA index pain (0-500) and overall arthritis pain intensity* (0-100).

Secondary: WOMAC stiffness and physical function* (0-1700).

Morphine once daily and morphine twice daily both reduced pain and improved several sleep measures when compared with placebo. Analgesic efficacy was comparable between once daily and twice daily formulations.

Moran
1991
UK
Crossover

Quality:2

Rheumatoid Arthritis

20 (16)

CR Morphine 20 – 120 mg/d for 2 wk

Primary: Pain intensity* (100-mm VAS) 

Secondary: FIHAQ*, RS, GSS.

Although only 4 patients completed the study, results showed a significant improvement in pain in those taking morphine.

Moulin
1996
Canada
Crossover

Quality:4

Musculoskeletal pain

61 (18)

SR Morphine 30 – 120 (mean 83.5) mg/d for 6 wk

Primary: Pain intensity* (10-cm VAS)  

Secondary:  Pain relief, MPQ, Drug liking, rescue medication, SCL-90, POMS, SIP, PDI*, HSCS, patient’s preferences.

On VAS of pain, the morphine group showed a reduction in pain intensity relative to placebo in period I and this group also fared better in a crossover analysis of the sum of pain intensity differences from baseline. No other significant differences were detected.

Hale
2007
USA
Parallel (Enrichment)

Quality:2

Low-back pain

143 (76)

Oxymorphone ER 20-260 (mean 87.2, median 60 mg/d)o for 12 wk

Primary: change in average pain intensity (VAS) from baseline to final study visit*

Secondary: 24-h pain intensity, use of medication, patients and physicians overall satisfaction.

Pain intensity increased significantly more for patients randomized to placebo than for patients who continued their stabilized dose of oxymorphone. The increase from baseline to final visit was 31.6 mm for placebo and 8.7 mm with oxymorphone.

Matsumoto
2005

USA
Parallel

Quality:4

Osteoarthritis

491 (222)

A) Oxymorphone ER 40 mg bid*

B) Oxymorphone ER 20 mg bid

C) Oxycodone CR 20 mg bid

Duration: 4 wk

Primary: Pain intensity (VAS) at week 3

Secondary: Pain intensity from pain diary at wk 4*, WOMAC, patient and physician global assessments, drop outs due to lack of analgesia, sleep assessment, quality of life physical* and mental components (SF-36.

The primary end point showed a significant difference in favour of oxymorphone over placebo. Compared to placebo, both Oxymorphone 20 and 40 mg produced greater reductions in the WOMAC subscales at weeks 3 and 4.

Kivitz
2006
USA
Parallel

Quality:4

OA hip or knee

370 (172)

A) Oxymorphone ER 10 mg bid for 2 wk

B) Oxymorphone ER 20 mg bid for 1 week, then 40 mg bid for 1 wk

C) Oxymorphone ER 20 mg bid for 1 wk, then 50 mg bid for 1 wk.*

Primary: Arthritis pain intensity from VAS at week 1 and 2*.

Secondary: WOMAC*, SF-36, chronic pain sleep inventory (CPSI), vital signs, clinical laboratory parameters, and adverse events.

Oxymorphone ER administered twice daily for 2 weeks produced dose-related reductions in arthritis pain intensity and improvements in physical function.

Zautra
2005
USA
Parallel

Quality:3

Moderate to severe pain due to OA

107 (71)

A) CR Oxycodone 10 mg bid for 2 wk

They reported the results at 2-weeks, but the study lasted for 3 months.

Primary: Average 24 hour pain rating* (average of twelve daily reports was used for the 2-weeks posttest score on pain).

Secondary: Positive and negative Watson’s scale for affect. Vanderbilt multidimensional pain coping inventory. Coping efficacy and arthritis helplessness.

Oxycodone administered twice daily for 2 weeks demonstrated a significant reduction not only in 24 hour pain intensity but also in the other variables (coping and affect) favouring the active group. A significant drop out rate was observed (75% and 59% in the placebo and active group respectively)

Portenoy
2007

USA
Parallel
(Enrichment)

Quality:5

Acute on chronic low-back pain,

77 (3)

Fentanyl buccal tablets, maximum dose 800 mcg per episode.

Duration 3 wk

Primary:  electronic pain diary, 0 to 120 minutes after pain crisis. SPID-60 was the sum of pain intensity differences for the first 60 min.

Secondary:  proportion of breakthrough pain episodes with improvement >33% and 50%, pain relief at each posttreatment time point, proportion of episodes in which meaningful pain relief was obtained, time to meaningful pain relief, and proportion of episodes that required the use of supplemental medication.

SPID-60 was significantly better in the fentanyl group. All secondary measures also favoured fentanyl.

Langford
2006

Multicenter in Europe
Parallel

Quality:4

Osteoarthritis of hip and knee. Moderate to severe pain.

416 (217)

Transdermal fentanyl (25-100 mcg) for 6 wk

Primary: pain relief* (average area under the curve of the VAS scores over time).

Secondary: WOMAC* score and its components.

Transdermal fentanyl provided significantly better pain relief than placebo, as demonstrated by the primary area under the curve for VAS scores -20 in the TDF group versus -14.6 in the placebo group. TDF was also associated with significantly better overall WOMAC scores and pain scores.

Landau
2007
UK and USA
Parallel
(Enrichment)

Quality:4

Non-cancer pain (49% low back )

267 (12)

Buprenorphine transdermal (5-20 mg) for 2 wk

Primary: proportion of subjects with ineffective treatment*

Secondary: time to ineffective treatment, proportion of subjects who reached ineffective treatment or discontinued for any reason, amount of escape medication used.

The proportion with ineffective treatment was lower in the buprenorphine group than in the placebo group (51.2% vs 65%). The odds of ineffective treatment were 1.79 times greater for placebo than buprenorphine.

3. Placebo-controlled (Fibromyalgia pain)

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Russell
2000

USA
Parallel (Enrichment)

Quality:5

Fibromyalgia

69 (1)

Tramadol 50 – 400 mg/d for 6 wk

Primary:  Nº of patients exiting due to inadequate pain relief.

Secondary: Pain intensity* (10-cm VAS), pain relief, tender-point count, myalgic score, FMIQ* (0-100).

Twenty (57.1%) patients in the tramadol group successfully completed the double-blind phase compared with nine (27%) in the placebo group.

Bennett 2003
USA
Parallel

Quality:4

Fibromyalgia

315 (177)

Tramadol 37.5 – 300 mg/d + acetaminophen 325 – 2600 mg/d for 11.5 wk

Primary: Cumulative time of discontinuation due to lack of efficacy.

Secondary: Pain Intensity* (100-mm VAS), pain relief, tender-point count, myalgic score, FMIQ*, SF-36,12-SQ.

Discontinuation was less common in the tramadol group (48%) compared with the placebo group (62%). Tramadol treated patients also had significantly less pain at the end of the study, better pain relief and better FMIQ scores.

4. Placebo-controlled (Mixed pain)

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Maier 2002
Germany Crossover

Quality:5

Neuropathic (67%) Nociceptive (32%)

49 (13)

SR Morphine 10 – 180 mg/d for 1 week (mean 114 mg/d)

 

Primary: Pain intensity* (0-10 NRS).

Secondary: Tolerability of pain, sleep quality, physical fitness, mental state and mood, PDI*, symptom complain.

At the first wk, 44% under morphine and 0% under placebo had full responsiveness. After 2 wk 40% under morphine and 2% under placebo had full responsiveness.

5. Opioids versus other analgesics

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Gobel
1995

Germany
Parallel

Quality:1

Postherpetic neuralgia

35 (14)

Tramadol
200 – 600 mg/d for 6 wk

Control: Clomipramine
50 – 100 mg/d with or without Levomepromazine 25–50 mg/d

Primary:  Pain intensity*(5-point verbal rating scale).

Secondary: Psychological and physical condition.

In both groups the pain intensity decreased over the 6-wk treatment period. (Reviewers’ comments: no significant difference between groups). There were no essential differences in the current psychic/physical conditions during tramadol treatment.

Pavelka 1998
Czech
Republic

Crossover

Quality:5

Osteoarthritis hip and knee

60 (6)

Tramadol 150 - 300 mg/d for 4 wk

Control: Diclofenac 75 - 150 mg/d

Primary: WOMAC OA index (pain*, stiffness and physical disability*).

Secondary: Drug preference.

Both treatments modestly improved median pain intensity, paralleled by an improvement in functional parameters, and there were no statistically significant differences between the groups.

Beaulieu 2008
Canada
Parallel

Quality:5

OA knee or hip

129 (32)

CR Tramadol
200 - 400/d for 6 wk

Control: SR diclofenac 75mg/d for 6 wk

Primary: daily pain intensity by VAS* and WOMAC* pain subscale.

Mean change for WOMAC pain subscale was 73.2 ± 99.9 for tramadol and 80,2 ± 108 for diclofenac. Mean change for overall VAS pain score was 17.3 ± 22.6 for tramadol and 16.4 ± 24.4 for diclofenac.

Parr 1989
USA
Parallel

Quality:3

Pain in ≤2 joints.

846 (213)

D&A: dextropropoxyphene 1080 mg/d  + acetaminophen 1950 mg/d for 4 wk

Control: SR Diclofenac 100 mg/d

Primary:  Pain intensity* (100-mm VAS)

Secondary: Nottingham Health Profile. (NHP)*, energy, sleep, social isolation and emotional reactions.

Pain as measured by VAS showed 8% greater pain reduction with diclofenac as compared with D&A. Physical mobility as measured by the NHP improved by 13% more with diclofenac as compared with D&A.

Salzman and Brobyn
1983 (A)

USA
Parallel

Quality:4

Osteoarthritis

57 (11 at 1 wk) in Salzman’s group and 57 (7 at 1 wk) in Brobyn’s

Propoxyphene 250 mg/d for 24 wk

Control: Suprofen 800 mg/d

Primary:  Pain intensity* (5-point numerical scale).

Secondary: Pain relief, global improvement.

Both suprofen and propoxyphene produced a considerable reduction in pain intensity from baseline after only 1 wk treatment. This beneficial effect did not diminish with continued therapy. Further improvement occurred in both groups by 24 wk.

Glowinski 1999
France
Parallel

Quality:3

Rheumatoid Arthritis

60 (2)

Codeine 90 mg/d + acetaminophen 1500 mg/d for 1 week.

Control: Diclofenac 100 mg/d + placebo.

Primary: Global efficacy (5-point verbal scale).

Secondary: Pain intensity* (100-mm VAS), Impairment of activity (4-point scale), duration of morning stiffness, number of awakenings.

Analgesic efficacy was not significantly different between the two groups on all criteria.

Kjaersgaard-Andersen 1990
Denmark
Parallel

Quality:3

Osteoarthritis hip

161 (64)

Codeine 180 mg/d + acetaminophen 3 g/day for 4 wk

Control: Acetaminophen

3 g/day. Rescue Medication: Ibuprofen tablets 400 mg

Primary:  Daily intake of rescue medication.

Secondary: Daily and weekly hip pain.

At 7 days, the addition of codeine was better than acetaminophen alone. After this, there was no difference.

Jamison 1998
USA
Parallel

Quality:2

Back pain

36 (3)

A) Oxycodone + SR Morphine 90 mg/d for 16 wk(*)

B) SR Oxycodone 40 mg/d for 16 wk

Control: Naproxen 1000 mg/d.

Primary: Pain intensity* (0-100 scale).

Secondary: Mood. Level of activity, Number of hours and amount of study medication.

Both opioid groups had significantly less pain and emotional distress than the naproxen-only group. No differences in activity level or hours of sleep were found.

Vlok 1987
South Africa
Crossover

Quality:4

Osteoarthritis

31 (3)

Codeine 20 mg/d  + Ibuprofen 400 mg/d  + acetaminophen 500 mg/d for 4 wk

Control: Ibuprofen 1200 mg/d

Primary: Pain intensity (VAS)

Secondary: PAD, drug choice.

Combination of codeine with ibuprofen with acetaminophen was better than ibuprofen alone.

Raja 2002(b)
USA
Crossover

Quality:4

Postherpetic neuralgia

76 (32)

CR morphine up to 240 mg/d for 6 wk. Methadone was an alternative opioid.

Control: Nortriptyline up to 160 mg/d. Desipramine was an alternative antidepressant

Primary: Pain intensity* (0-10 NRS).

Secondary: Pain relief, cognitive function, MPI* (physical functioning subscale), sleep, mood, global preference.

The trend favouring opioids over tricyclic antidepressants fell short of significance and reduction in pain with opioids did not correlate with that following tricyclics.

Gilron 2005
Canada
Crossover

Quality:4

35 diabetic neuropathy and 22 postherpetic neuralgia.

57 (16)

A) SR morphine maximum tolerated for 5 wk.

B) SR morphine maximum tolerated combined with gabapentin for 5 wk

C) Gabapentin maximum tolerated for 5 wk

Primary: Pain intensity (0-10 NRS).

Secondary: SF-MPQ, Maximal tolerated doses, Mood (BDI), SF-36, Mental Status (Mini-Mental), and global pain relief.

Mean pain intensity at the maximal tolerated dose was 4.49 with placebo, 4.15 with gabapentin, 3.7 with morphine and 3.06 with gabapentin-morphine combination. Total scores in SF-36 were lower with gabapentin-morphine combination than placebo or each drug alone.

Wu 2008
USA
Crossover

Quality:4

Postamputation pain

60 (25)

A) SR Morphine 15 - 180 mg day for 6 wk

B) Mexiletine: 75 – 1200 mg day for 6 wk

Primary: Average change in overall pain intensity from the baseline to the last week of maintenance therapy using 0-10.

Secondary: Pain relief (0-100%) and the interference and general activity subscales from the MPI.

Morphine treatment provided lower pain scores compared with placebo and mexiletine. The mean percent pain relief during treatment with mexiletine, and morphine was 30 and 53%, respectively.

Khoromi 2007
USA
Crossover

Quality:1

Chronic lumbar radiculopathy (sciatica)

55 (27)

 

A) SR morphine 15-90 mg/d

B) Nortriptyline 25-100 mg/d

C) Combination

Duration: 9 wk

Primary: Average leg pain during the two weeks.

Secondary: Global pain relief, ODI, BDI and SF-36.

In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Frank 2008
UK
Crossover

Quality:3

Neuropathic pain

96 (32)

A) Dihydrocodeine maximum 240 mg/d for 14 wk

B) Nabilone maximum 2 mg/d for 14 wk

Primary: difference in pain (VAS) computed over the last 2 weeks of each treatment period.

Secondary: change in mood, quality of life, sleep and psychometric function.

The mean score was 6.0 mm longer for nabilone than for dihydrocodeine in the available case analysis and 5.6 mm in the per protocol analysis. Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone. Nabilone was significantly superior to dihydrocodeine on the SF-36 (role-physical).

6. N of 1 randomized trial

Study Country Design Quality Population Number randomized (drop-outs) Interventions and comparison groups Outcomes: Primary and Secondary Results (as reported in the studies)

Sheather-Reid
1998

Australia

Quality:3

Regional cervicobrachial pain

8 (3)

A) Codeine 120 mg/d for 4 wk

B) Ibuprofen 800 mg/d for 4 wk

C) Placebo for 4 wk

Primary: Pain intensity (VAS).

Secondary: Change in pain, uptime, and hours of sleep.

In none of the 5 subjects who completed the 12-week trial was analgesic efficacy of either drug shown.

* Data used for meta-analysis; ADL: Activity of Daily Living, BDI = Beck Depression Inventory, BPI = Brief Pain Inventory, BSS = Brief Stress Scale, CR = controlled-release, DMARD= Disease-Modifying Anti Rheumatic Drug, MPI = Multidimensional Pain Inventory, NNT: number needed to treat, NRS = numeric rating scale, ODI = Oswestry Disability Index, PES = Pain Experience Scale, POMS = Profile of Mood State, PDI = Pain Disability Index, PRSS = Pain-Related Self statement Scale, SDS = Self-Rating Depression Scale, SF-36 = Short Form 36 Health Survey, SR = sustained release, VAS = visual analog scale, WHYMPI = West Haven–Yale Multidimensional Pain Inventory