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Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia

  1. Michael PT Lunn1,*,
  2. Richard AC Hughes2,
  3. Philip J Wiffen3

Editorial Group: Cochrane Neuromuscular Group

Published Online: 3 JAN 2014

Assessed as up-to-date: 19 NOV 2013

DOI: 10.1002/14651858.CD007115.pub3


How to Cite

Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD007115. DOI: 10.1002/14651858.CD007115.pub3.

Author Information

  1. 1

    National Hospital for Neurology and Neurosurgery, Department of Neurology and MRC Centre for Neuromuscular Diseases, London, UK

  2. 2

    National Hospital for Neurology and Neurosurgery, MRC Centre for Neuromuscular Diseases, London, UK

  3. 3

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK

*Michael PT Lunn, Department of Neurology and MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. michael.lunn@uclh.nhs.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 3 JAN 2014

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Characteristics of included studies [ordered by study ID]
Arnold 2004

MethodsRandomised, double-blind, placebo-controlled, parallel group trial of duloxetine in fibromyalgia


Participants207 men or women over 18 years who fulfilled American College of Rheumatology criteria for fibromyalgia, and scoring 4 or more on the pain intensity item of the Fibromyalgia Impact Questionnaire (FIQ)


InterventionsDuloxetine 60 mg twice daily versus placebo for 12 weeks with a 20-day titration phase


OutcomesFollow-up at 12 weeks

Outcomes:

  • FIQ pain score
  • Short Form 36 Health Survey (SF-36)
  • Brief Pain Inventory


NotesGreater use of antidepressants in the placebo group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAssignment to treatment groups was determined by a computer-generated random sequence

Allocation concealment (selection bias)Low riskUsed an interactive voice response system

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind for all assessments in 12-week therapy phase, Investigators adjusted the number of placebo capsules similarly to maintain the blinding. Single-blind in run-in phase

Incomplete outcome data (attrition bias)
All outcomes
High risk46/104 (44%) in duloxetine and 37/103 (36%) in placebo group discontinued treatment but all dropouts accounted for and LOCF

Selective reporting (reporting bias)Unclear riskAs above in incomplete outcome data

Other biasLow riskMore use of antidepressants in the placebo group but this would bias against the treatment arm

Arnold 2005

MethodsRandomised, double-blind, placebo-controlled, parallel group trial of duloxetine in fibromyalgia


Participants354 participants

Women only, ≥ 18 years of age who met criteria for primary fibromyalgia as defined by the American College of Rheumatology, and had a score of ≥ 4 on the average pain severity item of the Brief Pain Inventory (BPI) at randomisation


InterventionsDuloxetine 60 mg daily, duloxetine 60 mg twice daily and placebo for 12 weeks


Outcomes
  • BPI (average pain severity)
  • Short Form 36 Health Survey (SF-36)
  • BPI interference scale


NotesCompany sponsored and run trial. Fibromyalgia Impact Questionnaire abandoned in favour of BPI


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom assignment of women who met entry criteria following the screening phase to one of three treatment groups: duloxetine 60 mg daily, duloxetine 60 mg twice daily (forced titration from 60 mg daily for 3 days to 60 mg twice daily), or placebo, with randomisation in a 1:1:1 ratio. Random assignment of the participants to treatment groups occurred within two stratified groups, those with and those without current major depressive disorder

Allocation concealment (selection bias)Unclear riskProbably low risk of bias as previous trial used an adequate method

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh proportion of dropouts: 138 (39%) participants withdrew during the 12-week therapy phase, 41 (35%) from the duloxetine 60 mg daily group, 45 (39%) from the duloxetine 60 mg twice daily group, and 52 (43%) from the placebo group (P = 0.407). Matched across groups but a high rate of loss

"Partial intention to treat analysis". Efficacy analyses include all randomised participants with a baseline and at least one post-baseline visit with efficacy data, while safety analyses included all randomised participants

Selective reporting (reporting bias)Unclear riskSee incomplete outcome data above

Other biasLow riskLilly study. No other bias identified

Arnold 2010

MethodsPhase IV randomised, double-blind (subject, caregiver, investigator, outcomes assessor), placebo-controlled, parallel assignment safety and efficacy study of duloxetine in fibromyalgia


ParticipantsMen or women

  • Aged 18 and older who meet criteria for fibromyalgia as defined by the American College of Rheumatology
  • With a score of at least 4 on the average pain item of the Brief Pain Inventory (BPI) (modified short form) at visits 1 and 2
  • All females must test negative for pregnancy at the time of enrolment
  • A degree of understanding such that the potential participant can provide informed consent, complete protocol required assessments and communicate intelligibly with the investigator and study coordinator


InterventionsDuloxetine 60 to 120 mg daily for 24 weeks


OutcomesTime frame for all outcome measures 24 weeks

Primary outcome

  • Patient Global Impression of Improvement (PGI-I)


Secondary outcomes

  • BPI
  • Multidimensional Fatigue Inventory
  • Beck Depression Inventory-II (BDI II)
  • Clinical Global Impressions of Severity (CGI-S)
  • Beck Anxiety Inventory
  • SF-36 (Short Form Health Survey)
  • Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire
  • Anxious Likert Scale
  • Sleep Likert Scale
  • Pain Likert Scale
  • Stiffness Likert Scale
  • Mood Likert Scale
  • Columbia Suicide Severity Rating Scale


NotesCompleted and published


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned 1:1 in a double-blind fashion to duloxetine 60 mg once daily or placebo by a computer-generated random sequence using an IVRS

Allocation concealment (selection bias)Low risk"Double blind". "Variable transition to active treatment strategy…thereby blinding the onset of active treatment to reduce the patient's expectation of experiencing side effects"

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo comment on formulation of drug or placebo but almost certainly double blinded both in up and down titration. However, significantly more participants on duloxetine withdrew with adverse effects

Incomplete outcome data (attrition bias)
All outcomes
Low riskAccounted for as much as possible. High dropout rate (> 30%). Employs ITT - use of a "restricted maximum likelihood-based [mixed effects model repeated measures approach] analysis accounts for bias caused by non-random missing data due to early discontinuation because of adverse events or lack of efficacy better than LOCF"

Selective reporting (reporting bias)Low risk"Patient Global Impression - severity (PGI-S) only assessed at baseline". Otherwise, paper reports all results

Other biasUnclear riskLilly trial. 93.2% female participants, similar to all fibromyalgia studies

Arnold 2012

MethodsRandomised, double-blind, placebo-controlled, parallel group study of duloxetine in fibromyalgia


ParticipantsWomen and men > 18 years of age who met the American College of Rheumatology 1990 criteria for primary fibromyalgia and had a score of > 4 on the average pain severity item of the Brief Pain Inventory (BPI)-Modified Short Form. Patients with or without major depressive disorder or generalised anxiety disorder, as defined by the DSM-IV and confirmed by the MINI were included.


InterventionsDuloxetine 30 mg capsules or placebo for 12 weeks


OutcomesPrimary outcome

  • 24 hour pain severity on the BPI-Modified Short Form


Secondary outcomes

  • Patient global impression of improvement
  • Fibromyalgia Impact Questionnaire
  • response rate (30% or 50% reduction in BPI average pain severity)
  • BPI pain severity items (pain right now, worst pain, least pain) and BPI interference score
  • Clinical Global Impression - Improvement scale (CGI-I) for depression
  • Beck Depression Inventory II
  • Beck Anxiety Inventory
  • Short Form Health Survey (SF-36)
  • adverse events (treatment emergent, serious, vital signs and analytes, Columbia Suicide Severity Scale


NotesLilly study. No other bias identified


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation by a computer-generated random sequence using an interactive voice response system (IVRS)

Allocation concealment (selection bias)Unclear riskUnclear

Blinding (performance bias and detection bias)
All outcomes
Low riskThe duloxetine and placebo capsules were identical in appearance to maintain the blinding. Participants and investigators were kept blinded to the rescue criteria and dose increase; site personnel entered the major depressive disorder status at baseline and the CGI-I for Depression scores through IVRS at every visit

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 2 dropouts, both from duloxetine group and likely to have been of minimal significance

Selective reporting (reporting bias)Low riskMost outcomes presented except individual BPI severity items (worst pain, least pain, pain right now). However, no other outcomes with significant effect in completely negative trial

Other biasLow riskLilly study. No other bias identified

Brecht 2007

Methods8-week, randomised, double-blind, placebo-controlled, parallel-group efficacy and safety study of duloxetine in the treatment of pain of unknown aetiology in people with major depressive disorder


ParticipantsWomen or men > 18 with major depressive disorder defined by DSM-IV. At baseline, depression score of > 20 on the MADRS and at least moderate pain on Brief Pain Inventory Short Form (BPI-SF) - 3 or higher for "24 hour average pain". Participants were also devoid of any other diagnosed pain syndrome as per a medical history


InterventionsDuloxetine 60 mg versus placebo for 8 weeks


OutcomesPrimary outcome

  • Mean change in the BPI-SF 24 hour pain during 8 weeks of treatment


Seconday outcomes

  • Response rates to individual BPI severity items (worst pain, least pain, pain right now), and interference items (30% or more from baseline and sustained if maintained response from response definition to 8-week completion)
  • MADRS (max score 60, reduction of 50% defined as response, sustained as above)
  • Clinical Global Impression - Severity scale (CGI-S)
  • Clinical Global Impression - Improvement scale (CGI-I)
  • Patient Global Impression of Improvement (PGI-I)
  • The Symptom Checklist-90-R (SCL-90-R),
  • adverse events, treatment emergent adverse events, vital signs, laboratory parameters


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomised"

Allocation concealment (selection bias)Unclear risk"Double blind"

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double blind"

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT using all participants with 1 dose of drug. 25% dropout rate

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskCompany sponsored trial

Chappell 2008

MethodsSix-month, randomised, double-blind, placebo-controlled, clinical trial of duloxetine in fibromyalgia


ParticipantsMale and female outpatients were eligible for the study if they were ≥ 18 years of age, met criteria for fibromyalgia as defined by the American College of Rheumatology, with or without major depressive disorder

No criteria for pain level at entry


InterventionsDuloxetine - variable dose. Started at 60 mg (30 mg run in period over 1 week), randomised increase to 120 mg after 13 weeks if not > 50% reduction in pain on BPI average


Outcomes
  • BPI-I at > 12 weeks. No data given for less than 12 weeks although "statistically significant" P values quoted without figures at weeks 1, 2, 4, 6 and 8 BUT NOT 13, then week 18
  • Short Form Health Survey (SF-36)
  • Patient Global Impression of Improvement
  • Fibromyalgia Impact Questionnaire (FIQ)
  • Clinical Global Impression - Severity scale (CGI-S)
  • Multidimensional fatigue inventory
  • Hospital Anxiety and Depression Scale (HADS)
  • Hamilton Depression Rating Scale (HAMD)
  • Beck Depression Inventory –II
  • Sheehan Disability Scale
  • EQ-5D


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated random sequence within each study centre stratified by major depressive disorder

Allocation concealment (selection bias)Low riskDouble-blind

Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants "blinded", but not clear how the study managed dose escalations and decreases and whether blinding was maintained

Incomplete outcome data (attrition bias)
All outcomes
High risk37.6% to 38.6% discontinuations, significantly different in lack of efficacy only. Investigators used LOCF and MMRM to correct for dropouts

Selective reporting (reporting bias)Low risk30% improvement in BPI-average added post hoc

Other biasUnclear riskLilly sponsored trial

Significant unexplained treatment by investigator interaction

Gao 2010

MethodsPhase III randomised, double-blind (subject, caregiver, investigator, outcomes assessor), placebo-controlled, parallel assignment safety and efficacy study of duloxetine in painful diabetic neuropathy


Participants215 participants

Men or women, aged 18 to 75, pain due to bilateral peripheral neuropathy caused by type I or type II diabetes with the pain beginning in the feet, and present for at least 6 months. Score of 4 or greater on the Brief Pain Inventory (BPI) on the 24-hour average pain item


InterventionsDuloxetine 60 mg daily for 12 weeks


OutcomesPrimary outcome

  • BPI 24-hour average pain score (efficacy of duloxetine 60 to 120 mg daily)


Secondary outcomes

  • BPI worst pain, least pain, and current pain severity and average of 7 interference scores
  • Clinical Global Impression of Severity
  • Patient Global Impression of Improvement
  • EuroQoL Questionnaire - 5 dimensions
  • Discontinuation rates
  • Tolerability of morning versus evening dosing, spontaneously reports adverse events
  • Athens Insomnia Scale 8-item and 5-item
  • Adverse events
  • Vital signs
  • Laboratory measures


NotesClosed and completed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomly assigned

Allocation concealment (selection bias)Low risk"Double blind". Study medication in capsules…or matching placebo'

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
Low risk15.6% to 17.9% dropout rate but ITT using LOCF and MMRM approach to minimise bias

Selective reporting (reporting bias)Low riskSelective use of MMRM or LOCF depending upon outcome. However, all measures reported

Other biasLow riskLilly sponsored trial

No adjustment for multiple comparisons

Gaynor 2011a

MethodsRandomised, double-blind, placebo-controlled trial of duloxetine in people with major depressive disorder and painful physical symptoms


ParticipantsAdult (18 years of age) male or female outpatients were eligible ...if they met all of the following: a current episode of major depressive disorder according to the DSM-IV-TR and confirmed by the MINI with a history of at least one separate, previous episode of depression, and at both the screening and randomisation visits a MADRS total score of 20, and at least moderate pain with a score of 3 on the Brief Pain Inventory Short Form (BPI) average pain item, and a Clinical Global Impression of Severity (CGI-S) score 4. Painful symptoms were not allowed to have an identifiable underlying cause


InterventionsDuloxetine 60 mg once daily orally for 8 weeks vs placebo


Outcomes
  • BPI at 8 weeks
  • Patient reported global impression of improvement
  • Sheehan Disability Scale global functional impairment score


NotesGaynor 2011b identical in design - different patient group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised

Allocation concealment (selection bias)Unclear riskUnclear

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concerns

Selective reporting (reporting bias)Low riskNone

Other biasLow riskNone

Gaynor 2011b

MethodsA randomised, double-blind, placebo-controlled trial of duloxetine in people with major depressive disorder and painful physical symptoms


ParticipantsAdult (18 years of age) male or female outpatients were eligible ...if they met all of the following: a current episode of major depressive disorder according to the DSM-IV-TR and confirmed by the MINI with a history of at least one separate, previous episode of depression, and at both the screening and randomisation visits a MADRS total score of 20, and at least moderate pain with a score of 3 on the Brief Pain Inventory Short Form (BPI) average pain item, and a Clinical Global Impression of Severity (CGI-S) score 4. Painful symptoms were not allowed to have an identifiable underlying cause


InterventionsDuloxetine 60 mg once daily orally for 8 weeks vs placebo


Outcomes
  • BPI at 8 weeks
  • Patient reported global impression of improvement
  • Sheehan Disability Scale global functional impairment score


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'Randomised'

Allocation concealment (selection bias)Unclear riskUnclear

Blinding (performance bias and detection bias)
All outcomes
Unclear risk'Double Blind'

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concerns

Selective reporting (reporting bias)Low riskNone

Other biasLow riskNone identified

Goldstein 2005

MethodsRandomised, double-blind, placebo-controlled, parallel group, trial of duloxetine in painful diabetic neuropathy


Participants457 participants

Participants, at least 18 years of age, had daily pain due to polyneuropathy caused by type 1 or type 2 diabetes mellitus, which was present for a minimum of 6 months. This pain had to have begun in the feet with relatively symmetrical onset. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument (MNSI). Participants were required to have a minimum score of 4 on the 24-hour average pain score rated on an 11-point (0 to 10) Likert scale.


InterventionsDuloxetine 20 mg daily, 60 mg daily or 60 mg twice daily versus placebo for 8 weeks


Outcomes
  • 24-hour average pain score
  • SF-36
  • Patient Global Impression of Change,
  • Night pain


NotesCompany sponsored and run trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned in a 1:1:1:1 ratio by a computer generated random sequence

Allocation concealment (selection bias)Low riskParticipant numbers were assigned consecutively at each study site. The interactive voice response system was used to assign blister cards containing the study drug to each participant confirmed through interactive voice response system entry of a confirmation number on the card

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskAll analyses were undertaken as an ITT analysis. All participants were analysed in the safety analysis and all participants with at least one post entry data point were analysed in an ITT analysis. Dropout rate was 25% with significantly more in the higher dose treatment groups

Selective reporting (reporting bias)Unclear riskSee above

Other biasLow riskCompany sponsored and run trial

Kaur 2011

MethodsRandomised, double-blind, cross-over clinical trial comparing amitriptyline and duloxetine in painful diabetic neuropathy


Participants86 participants - 65 randomised to treatment in 1st arm, 58 of whom completed both arms

People of either sex with type 2 diabetes, aged between 18 and 75 years, who were on stable glucose-lowering medications during the preceding month and who had painful diabetic neuropathy for at least 1 month were considered for the study. The study enrolled people who had a pain score of > 50%, as assessed by visual analogue scale (VAS). Painful diabetic neuropathy was confirmed by 1) medical history, 2) a diabetic neuropathy symptom (DNS) score of > 1 point (7), 3) a Diabetic Neuropathy Examination (DNE) score of > 3 points (8), 4) a modified neuropathy symptom score (mNSS) (9,10), and 5) increased thresholds on the vibration perception test and monofilament test


InterventionsAmitiyptyline 10, 25 or 50 mg once daily at night or duloxetine, 20, 40 or 60 mg once daily at night

Intervention only 6 weeks before 2 week washout and cross-over to alternate arm. Participants commenced on lowest dose and then increased every 2 weeks to next dose if required by treating physician; thus potentially only 2 weeks on maximum dose. 48% of amitriptyline and 65% of duloxetine participants reached the highest dose of drug. 17% vs 5% of the participants preferred higher dose duloxetine to amitriptyline


OutcomesPrimary outcome

  • Patient's global assessment of efficacy by VAS (0 to 100)


Secondary outcomes

  • Short form McGill pain questionnaire (11)
  • 11-point Likert scale for pain (0 to 10)
  • DNE score
  • DNS score
  • mNSS
  • Hamilton Depression Rating Scale (HAMD)
  • change in sleep pattern (increased, unchanged or decreased)
  • Patient global impression of change


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised (computer generated randomisation of blocks of 4)

Allocation concealment (selection bias)Unclear riskAn independent person unrelated to the study carried out blinding and randomisation. Two separate companies provided medicines, so it is not clear that they were identical in appearance

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinded. Single physician assessment. "success of blinding was assessed by the accuracy of the physicians prediction at the end of the study" (34% correctly identified only)

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concerns

Selective reporting (reporting bias)High riskThe primary end point of the study was the reduction in the median pain score from baseline, (patient’s global assessment of efficacy by VAS (0 to 100 points)). Secondary end points included the assessment of pain by the short-form McGill Pain Questionnaire (11); an 11-point Likert scale for pain (0 = no pain and 10 = excruciating pain); change in sleep pattern (increased, unchanged, or decreased); overall improvement by DNE score, DNS score, mNSS, and the 24-point HAMD; and patient self evaluation of overall change on the basis of a 7-point Patient Global Impression of Change (PGIC) scale not reported in analysis.

Other biasHigh riskSignificant (but similar) carryover into period 2 despite 2 weeks' washout

Raskin 2005

MethodsRandomised, double-blind, placebo-controlled, parallel group trial in diabetic peripheral neuropathic pain


Participants348 participants

Participants ≥ 18 years, with pain due to bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. The pain had to begin in the feet with relatively symmetrical onset and be present for at least 6 months. Participants had to have a mean score of ≥ 4 when assessed for 24-hour average pain severity on the Michigan Neuropathy Screening Instrument (MNSI) 11-point Likert scale (from the patient diary prior to randomisation), and stable glycaemic control. Concomitant pain medications excluded.


InterventionsDuloxetine 60 mg daily or duloxetine 60 mg twice daily versus placebo for 12 weeks


Outcomes
  • 24-hour average pain severity
  • Patient global impression of clinical change,
  • pain at rest
  • Brief Pain Inventory (BPI) severity
  • Clinical Global Impression of Pain Severity scale (CGI-S)
  • Short Form McGill pain questionnaire
  • BPI interference scale


NotesCompany sponsored and run trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation performed at visit 3 in a 1:1:1 ratio. A computer-generated random sequence determined assignment to treatment groups, using an IVRS

Allocation concealment (selection bias)Low riskParticipants received either of (or a combination of, depending on their randomly assigned treatment) the following: 30 mg capsules of duloxetine hydrochloride or placebo capsules identical to duloxetine capsules. Participants randomly assigned to each treatment group were instructed to take two capsules (by mouth) every morning and every evening.

Treatment was assigned using IVRS

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts were 52/340 (15%). Analysis was by ITT

Selective reporting (reporting bias)Low riskSee above

Other biasLow riskLilly study. No other bias identified

Rowbotham 2012

MethodsPhase II, randomised, double-blind, placebo-controlled, single group assignment, safety and efficacy study comparing duloxetine, ABT-894 and placebo in diabetic neuropathic pain


Participants108 participants

Men and women 18 to 75

Inclusion criteria:

  • The subject must have a diagnosis of diabetes mellitus (type 1 or type 2) and a diagnosis of diabetic neuropathic pain
  • Participant's diabetic neuropathic pain must be present for a minimum of six months and should have begun in the feet with relatively symmetrical onset.
  • Participant has an HbA1c ≤ 9. Participants who have an HbA1c > 9 and ≤11 may be included in the study


InterventionsDrug: ABT-894, 1 mg, 2 mg, 4 mg twice daily
Drug: placebo
Drug: duloxetine 60 mg

Duration 8 weeks


OutcomesPrimary outcome

  • Efficacy of each ABT-894 dose (1 mg, 2 mg or 4 mg twice daily) versus placebo in the treatment of pain due to diabetic neuropathic pain (time frame: change from baseline to final 24-hour average pain score)


Secondary outcomes

  • Proportions of treatment responders; subjects who complete treatment period with 30% improvement (time frame: from baseline to final 24-hour average pain score)
  • Mean of 24-hour worst pain severity, average of night pain, and average of morning pain measured by the 11-point Likert scale and from participant's daily diary (time frame: weekly during treatment)
  • BP-(Short Form) including pain severity (time frame: at each visit from baseline to week 8)
  • Clinician Global Impression Severity scale (CGI-S) and Patient Global Impression of Change (PGIC) (time frame: at each visit from baseline to week 8) 


NotesPublished 2012


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants "were randomized 1:1 to each treatment arm via an interactive voice response system using a randomization schedule that was generated before study start"

Allocation concealment (selection bias)Low riskCareful attention to placebo and medication concealment noted

Blinding (performance bias and detection bias)
All outcomes
Low riskNo concerns

Incomplete outcome data (attrition bias)
All outcomes
Low riskAlmost 100% completed

Selective reporting (reporting bias)Low riskAll reported

Other biasLow riskNone identified

Russell 2008

MethodsRandomised, double-blind, placebo-controlled, parallel group trial in fibromyalgia


Participants520 participants

Female and male outpatients ≥ 18 years of age who met criteria for fibromyalgia as defined by the American College of Rheumatology. Participants were required to have a score ≥ 4 on the average pain severity item (in the past 24 hours) of the Brief Pain Inventory (BPI-modified Short Form at screening and at baseline. The study included people with or without current major depressive disorder and evaluated them for the presence of psychiatric disorders using the MINI. Prior to randomisation, the study required participants to discontinue any medications that might interfere with the evaluation of pain improvement, including analgesics (with the exception of up to 325 mg/day of aspirin for cardiac prophylaxis and paracetamol up to 2 g/day for pain), antidepressants, anticonvulsants, or other medications taken for fibromyalgia or pain


InterventionsDuloxetine 20 mg daily, 60 mg daily or 60 mg twice daily versus placebo for 6 months


Outcomes
  • BPI average pain severity score
  • Short Form 36 Health Survey (SF-36)
  • patient global impression of clinical change


NotesCompany sponsored and run trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated random sequence determined assignment to treatment groups and the study randomly assigned each stratum (depressed and non-depressed) within sites to achieve a relative balance across treatments

Allocation concealment (selection bias)Unclear riskUnclear although other trials from the same group have been adequate

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
High risk35% to 40% dropout at the 3 month interim analysis phase and up to 46% dropout for the 6 month phase. "Intention-to-treat unless otherwise specified". Safety analyses in all participants and others with data for at least 1 measure

Selective reporting (reporting bias)Unclear riskSee above

Other biasLow riskLilly study. No other bias identified

Tesfaye 2013

MethodsRandomised, double-blind, placebo-controlled, parallel group enrichment trials with three phases comparing duloxetine to pregabalin in painful diabetic neuropathy


Participants401 participants treated with duloxetine and 403 with pregabalin

Included participants had pain due to bilateral peripheral neuropathy (caused by type 1 or type 2 diabetes mellitus. Pain must have begun in the feet, with relatively symmetrical onset. Daily pain should have been present for more than 3 months (assessed by questioning the patient).
• Score of at least 4 on the 24-hour average pain severity score on an 11-point Likert scale (on Brief Pain Inventory Modified Short Form (BPI-mSF)) at screening and at randomisation
• Participants not receiving treatment for diabetic peripheral neuropathic pain or received treatment for diabetic peripheral neuropathic pain, with a drug other than pregabalin or duloxetine, and completed the required washout
• Participants never received treatment with duloxetine or pregabalin (short courses of less than 15 days of treatment, at any time previously, allowed)
•Stable glycaemic control, as assessed by a physician investigator, and HbA1c less than or equal to 12% at screening


InterventionsPregabalin titrated to 150 mg twice daily was compared to duloxetine titrated to 60 mg once daily (with placebo tablets to maintain blind between treatments) and treated in study phase II for 8 weeks. A third phase of non-responding participants entered study phase III not included in this analysis


OutcomesPrimary outcome

  • 24-hour average pain on BPI-mSF VAS. Response rates of 30%, 50% or 2-point reduction collected at all visits


Secondary outcomes

  • BPI-SF items as other studies
  • Clinical Global Impression - Improvement scale (CGI-I)
  • Patient Global Impression - Improvement (PGI-I)
  • Neuropathic Pain Symptom Inventory (NPSI) and 5 subscores
  • HADS
  • 24-hour average pain on the BPI-mSF for period 2 of trial (initial therapy)
  • Treatment emergent adverse events, serious adverse events, vital signs, laboratory values, Beck Depression Inventory II (BDI-II) to assess suicide risk


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised 1:1:1:1 in 4 parallel groups based on a computer generated sequence using IVRS

Allocation concealment (selection bias)Unclear riskUnclear - although all drugs and placebo were similar and the allocation stratified by site, does not explicitly deal with concealment

Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial maintained blinding by using over-encapsulated duloxetine and pregabalin capsules, matching placebo and an identical dosing regimen for all groups in terms of numbers and timing of capsules

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropout in Phase II 17%, 9% with adverse events. All analyses performed on ITT (baseline + 1 measure for outcomes, all randomised for adverse events) with MMRM - however no statement as to whether LOCF or BOCF used

Selective reporting (reporting bias)High riskSome partial reporting of outcomes (for example NPSI subscores not tabulated, PGI-I and CGI-I in figure form only and differences of reporting between phase II and phase III outcome reporting

Other biasHigh riskLilly designed, interpreted, wrote and submitted. Ghost written by professional writer for company

Vranken 2011

MethodsStratified, randomised, double-blind, placebo-controlled, parallel group study of patients with severe central neuropathic pain of more than 6 months duration from cerebrovascular or spinal cord lesions


Participants48 participants aged 18 years or older with > 6 month severe neuropathic pain from cord or cerebrovascular cause, > 6 on visual analogue scale (VAS) (10 points), which started after sustaining the lesion and with the distribution of pain concomitant with the somatosensory system involvement. The trial allowed other medication if doses were stable for 6 weeks, except other antidepressants, which had to be stopped more than 30 days prior to receiving study medication


InterventionsDuloxetine or placebo for 8 weeks. Duloxetine 60 mg at start. Increased if participants did not meet criteria of > 1.8 points improvement on VAS. At week 8 and study end 15 participants on 120 mg and 8 participants on 60 mg


OutcomesPrimary outcome

  • Pain intensity on a 10-point VAS measured a baseline and weekly for the 8 weeks of the study. The final mean pain score was an average of 9 VAS scores measured over 72 hours in the last 3 days of the study


Secondary outcomes

  • Pain disability Index
  • EQ-5D
  • Short Form 36 Health Survey (SF-36) (beginning and end)
  • Patient Global Impression of Change (PGIC) (end of study only)
  • Quantitative sensory testing
  • Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSimple computerised random sampling (clorandm.exe) assigned study codes N = 1 to the placebo or duloxetine arm. Consecutive participants who met inclusion criteria were randomly assigned to treatment with flexible dose placebo or flexible dose duloxetine

Allocation concealment (selection bias)Low riskThe association between type of treatment and study code was only known to the Department of Epidemiology, Biostatistics and Bioinformatics and the hospital pharmacy department

Blinding (performance bias and detection bias)
All outcomes
Low risk

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Selective reporting (reporting bias)Low risk

Other biasLow risk

Wernicke 2006

MethodsRandomised, double-blind, placebo-controlled, parallel group trial of duloxetine in diabetic peripheral neuropathic pain


Participants334 participants

Men or women ≥ 18 years and with > 6 months diabetic peripheral neuropathic pain secondary to type 1 or 2 diabetes (distal and symmetrical). At randomisation, score > 3 on Michigan Neuropathy Screening Instrument and average > 4 on 24 hour pain scale. Stable glucose control and HBA1c < 12. Multiple exclusions including other pain medications except paracetamol and aspirin


InterventionsDuloxetine 60 mg daily, 60 mg twice daily or placebo for 12 weeks


OutcomesPrimary outcome

  • 24 hour average pain score (Likert 11-point)


Secondary outcomes

  • SF-36
  • BPI interference,
  • patient reported global clinical impression of change,
  • night pain,
  • clinical global impression - pain severity (CGI-S),
  • clinical global impression of change


NotesCompany sponsored and run trial


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was performed at the site level in that randomisation codes were assigned to sites in blocks, but there was no further stratification. Participants were randomly assigned to treatment in a 1:1:1 ratio. Assignment to a treatment group was determined by a computer-generated random sequence using an IVRS

Allocation concealment (selection bias)Low riskThe IVRS was used to assign blister cards containing study drug to each participant

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskDrop outs were 29/114 (25%) in duloxetine 60 mg daily, 34/112 (30%) in duloxetine 60 mg twice daily and 23/108 (21.3%) in the placebo group

Selective reporting (reporting bias)Unclear riskAn ITT principle was used in the analyses of all efficacy variables. For each efficacy variable, the analysis included all randomised participants with a baseline and at least one non-missing observation after baseline

Other biasLow riskLilly study. No other bias identified

Yasuda 2010

MethodsPhase III randomised, double-blind (subject, caregiver, investigator, outcomes assessor), placebo-controlled, parallel assignment, safety and efficacy study of duloxetine in diabetic peripheral neuropathic pain


Participants339 participants randomised

Male or female outpatients aged 20 years or older but less than 80 years at the time of consent:

  • with pain due to bilateral peripheral neuropathy induced by type 1 or 2 diabetes mellitus. The pain must have been present for at least 6 months and be evaluable in feet, legs, or hands
  • with HbA1c less than or equal to 9.0 percent at visit 1
  • in whom HbA1c had been measured 42 to 70 days before visit 1 and subsequent HbA1c levels have been within +/- 1.0 percent of the level at visit 1
  • with a mean of the 24-hour average pain severity scores (round off to a whole number) of 4 or higher, as calculated from the patient diary for 7 days immediately before visit 2


InterventionsDuloxetine 40 mg or 60 mg orally daily versus placebo for 12 weeks


OutcomesPrimary outcome

  • Reduction in average pain severity as measured by an 11-point Likert scale (time frame 12 weeks)


Secondary outcomes

  • Pain severity for worst pain and night pain as measured by an 11-point Likert scale (time frame 3 months)
  • Patient Global Impression of Improvement scale to measure the degree of improvement at the time of assessment (time frame 3 months) 
  • Brief Pain Inventory to measure the severity of pain (time frame 3 months)
  • Beck Depression Inventory-II (BDI-II) total score (time frame 3 months)
  • Safety (time frame 3.5 months)


NotesRecruiting


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAssigning table was prepared using Create Key Code 3.3. Participants were randomly assigned…' Stratified for pain, duration of diabetic peripheral neuropathy, diabetes type, study centre

Allocation concealment (selection bias)Unclear riskNo clear explanation of methodology

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double blind"

Incomplete outcome data (attrition bias)
All outcomes
Low risk10.2% to 16.9% dropout. All analyses using LOCF and MMRM

Selective reporting (reporting bias)Low riskNone identified

Other biasLow riskLilly sponsored

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Boyle 201228 days only

Brannan 20056 weeks of treatment only

Canovas 2007Not randomised or controlled

Chappell 2009Osteoarthritis of the knee - likely to cross over with Cochrane Musculoskeletal Group

Chappell 2011Osteoarthritis of the knee - likely to cross over with Cochrane Musculoskeletal Group

Goldstein 2004Trial of duloxetine in depression. Pain scales as secondary outcome measures only. It was not clear what sort of pain the participants had (for example musculoskeletal, neuropathic, headache) and the levels of pain at baseline were low compared to the included trials

Harrison 2013Four weeks treatment only in each group of 4 way crossover. Terminated early July 2013

Lavoie Smith 2012Abstract publication of Smith 2013

NCT00125892Open and then double-blind study comparing 2 doses of duloxetine 60 mg and 120 mg

NCT00266643The first part of this cross-over study was the only part of trial suitable for assessment (amitriptyline versus duloxetine) but only 4 weeks long - thus excluded

NCT00385671Open label

NCT00425230Was registered in clinicaltrials.gov - study terminated with no participants enrolled because no drug supplied

NCT00552682Open label duloxetine vs no treatment or pre-existing antidepressant

NCT00641719Open label extension of Yasuda 2010

NCT01451606Pelvic pain

Raskin 2005aNot a randomised controlled study but a report of 3 trials included in this review

Raskin 2006aNot a double-blind trial

Raskin 2006bOpen label study with dosage control only

Russell 2006Summary report of 3 studies included in this review

Skljarevski 2008Back pain - to be included in a Cochrane Back Group review - Back Group informed. Published in full format in 2009 European Journal of Neurology 16: 1041-8

Skljarevski 2009Back pain - to be included in a Cochrane Back Group review - Back Group informed

Skljarevski 2009aOpen label extension

Skljarevski 2010Back pain - to be included in a Cochrane Back Group review - Back Group informed

Skljarevski 2010bBack pain - to be included in a Cochrane Back Group review - Back Group informed

Smith 2013Duration of treatment only 4 weeks

Tanenberg 2011Open label - non blinded study

Vollmer 2011Measured outcomes at durations of less than eight weeks

Wernicke 2006bNot double-blind - extension of Goldstein 2005

Wu 2006Open study, not blinded

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT00603265

MethodsPhase II randomised, double blind, parallel assignment, safety and efficacy study

ParticipantsMale and female participants between 18 and 75 years of age

Diabetes mellitus (type I or II) that is documented to be under stable glycaemic control over a period of at least 3 months, as indicated by a HbAIc of ≤ 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication. Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy. Presence of daily pain due to DPN for at least 3 months. Score ≥ 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI). Average weekly pain score of ≥ 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs

InterventionsDrug: ADL5859
Drug: duloxetine
Drug: placebo

OutcomesPrimary outcome measures:

  • Change from baseline in mean NPRS (time frame: week 4)


Secondary outcome measures:

  • Change from baseline in the mean NPRS proportion of subjects with 30% reduction in average pain score (weekly)
  • Patient Global Impression of Change (PGIC) (time frame: week 4)
  • Change in Sleep Interference Scale (SIS) from baseline (time frame: week 4)
  • Change from baseline in the evening assessment of the 24-hour overall mean pain intensity score (time frame: weekly)
  • Change from baseline in NPRS at rest in the clinic (time frame: weekly)
  • Change from baseline in NPRS after walking 50 feet in the clinic (time frame: weekly)

NotesCompleted - no reference in Pubmed - no information on clinicaltrials.gov- e-mail written to company with request for information September 2012.

 
Characteristics of ongoing studies [ordered by study ID]
NCT00457730

Trial name or titleA randomised placebo controlled trial of duloxetine for central pain in multiple sclerosis

MethodsRandomised, double-blind (caregiver, investigator), placebo-controlled, parallel assignment safety/efficacy study

ParticipantsPeople with multiple sclerosis "who have central pain which is 4 or greater on a scale of 1-10. Patients must have experienced pain for 2 months or longer prior to beginning the study."

InterventionsDuloxetine 30 mg (10 capsules) for 1 week, titrated up to 60 mg (40 capsules) for 5 weeks and titrated back down to 30 mg for 1 week

Placebo for 7 weeks

OutcomesTime frame for all outcomes, week 2 and week 6

  • Weekly means of:
    • 24 hour average pain score
    • 24 hour worst pain score
    • sleep rating
  • Global Impression of Change
  • SF-36
  • Beck Depression Inventory
  • Average daily consumption of ibuprofen

Starting dateJanuary 2007

Contact informationBrown, Theodore R., M.D., MPH

Evergreen Healthcare Kirkland, Washington, United States, 98034

NotesNCT00457730 Lilly sponsored

NCT00619983

Trial name or titleThree way interaction between gabapentin, duloxetine, and donepezil in patients with diabetic neuropathy

MethodsRandomised, double-blind (subject, investigator, outcomes assessor), parallel assignment

ParticipantsMale or female. Diagnosis of diabetic neuropathy. Age 18 to 80

InterventionsGroup 1: donepezil 5 mg once per day for 12 weeks

Group 2: duloxetine 30 mg twice a day for 12 weeks

Group 3: combination of donepezil 2.5 mg and duloxetine 30 mg for 12 weeks

Group 4: placebo pills.

Gabapentin added to all groups at week 9

OutcomesPrimary:

  • Pain intensity measurements recorded twice daily, using McGill short form pain questionnaire on a handheld computer. The Visual Analog Pain Scale (VAS) served as the primary outcome measure (time frame: study completion (16 weeks)

Starting dateFebruary 2008 to July 2010

Contact informationRegina Curry, RN, CCRC

336-716-4294

recurry@wfubmc.edu

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States, 27157

NotesNCT00619983 Still recruiting 2013 - estimated completion July 2013

NCT01179672

Trial name or titleTreatment of patients with diabetic peripheral neuropathic pain in China: duloxetine versus placebo

MethodsRandomized, double blind (subject, investigator), placebo-controlled, parallel assignment, efficacy study

ParticipantsPeople over 18 years of age who present with pain due to bilateral diabetic peripheral neuropathy (type 1 or type 2 diabetes). Pain beginning in feet, relatively symmetrical onset, present daily for at least 6 months, confirmed by score of ≥ 3 on Michigan Neuropathy Screening Inventory

InterventionsDuloxetine 30 mg orally, once daily for 1 week; 60 mg once daily for next 11 weeks; 30 mg administered orally, once daily for 1 week during taper period

Placebo once daily for 12 weeks, once daily for 1 week during taper period

OutcomesPrimary:

  • Mean change in the pain severity score (measured from baseline to 12-week endpoint)


Secondary (changes measured from baseline to 12-week endpoint):

  • Mean change in night pain and worst pain
  • Mean change in the Brief Pain Inventory (BPI)-Severity scale
  • Mean change in the Clinical Global Impression - Severity (CGI-S) scale
  • Patient Global Impression of Improvement (PGI-I) scale
  • Mean change in the Sensory portion of the Short-form McGill pain questionnaire
  • Percentage of participants who experience ≥ 30%, ≥ 50% or ≥ 75% reduction from baseline to 12 week endpoint in average daily pain
  • Percentage of participants who experience ≥ 30%, ≥ 50% or ≥ 75% reduction from baseline in BPI-Severity average pain scores
  • Mean change in the Brief Pain Inventory (BPI) Interference scores
  • Mean change in the Sheehan Disability Scale (SDS)

Starting dateApril 2011

Contact informationEli Lilly and Company. Study director, tel: 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559

NotesNCT01179672

NCT01237587

Trial name or titleA study of duloxetine in adolescents with juvenile primary fibromyalgia syndrome

MethodsPhase III, randomised, double-blind (subject, caregiver, investigator, outcomes assessor), parallel assignment, safety/efficacy study

ParticipantsAged 13 to 17 years who meet criteria for primary juvenile primary fibromyalgia syndrome and have a score of greater than or equal to 4 on Brief Pain Inventory (BPI) average pain severity (Item 3) during screening

InterventionsBlinded period: 30 mg or 60 mg duloxetine or placebo once daily for 13 weeks

Open label extension: 30 mg or 60 mg duloxetine once daily for 26 weeks

OutcomesPrimary:

  • Change from baseline to 13 week endpoint in Brief Pain Inventory (BPI) modified short form-adolescent version 24 hour average pain severity item


Secondary:

  • Change from baseline to endpoint (13 weeks, 39 weeks extension phase) in Brief Pain Inventory (BPI) modified short form-adolescent version severity and interference items
  • Maintenance effect in acute phase responders on the Brief Pain Inventory (BPI) modified short form-adolescent version 24 hour average pain severity item (endpoint 13 weeks, 39 weeks extension phase)
  • Proportion of participants with ≥ 30% and ≥ 50% reduction in BPI 24 hour average pain severity score at 13 weeks
  • Change from baseline (endpoint 13 weeks, 39 weeks extension phase) in:
    • Pediatric Pain Questionnaire (PPQ) item scores
    • Clinical Global Impression - Severity (CGI-S): overall score and mental illness score
    • Functional Disability Inventory (FDI) child scale and rent scale
    • Children's Depression Inventory (CDI)
    • Multidimensional Anxiety Scale for Children (MASC)

Starting dateFebruary 2011

Contact informationEli Lilly and Company. Study Director: 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559

NotesNCT01237587

NCT01552057

Trial name or titleA phase III clinical trial of duloxetine in participants with fibromyalgia

MethodsRandomised, double-blind (subject, investigator), placebo-controlled, parallel assignment, safety/efficacy study

ParticipantsParticipants with fibromyalgia aged 20 to 74 years

Inclusion criteria:

  • fulfilling American College of Rheumatology 1990 criteria for fibromyalgia
  • pain severity ≥ 4 by Brief Pain Inventory (BPI) - average pain severity item (question 3)

InterventionsDuloxetine hydrochloride orally 60 mg for 15 weeks or oral placebo for 15 weeks

OutcomesChanges measured from baseline to 14 week endpoint

Primary:

  • 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score


Secondary:

  • Patient Global Impression - improvement (PGI-I) at endpoint
  • Clinical Global Impression of improvement (CGI-I) at endpoint
  • Fibromyalgia Impact Questionnaire (FIQ)
  • 36-Item Short-Form Health Survey (SF-36)
  • Beck Depression Inventory-II (BDI)
  • Widespread Pain Index and Symptom Severity in American College of Rheumatology Fibromyalgia Diagnostic Criteria 2010
  • Average Pain and Worst Pain Severity Score within 24-hours in Patient Diary
  • BPI Pain Severity Items and Interference Items of the BPI-Modified Short Form Score

Starting dateMarch 2012

Contact informationEli Lilly and Company, Shionogi. Tel: 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559

NotesNCT01552057

 
Comparison 1. Duloxetine versus placebo in the treatment of painful diabetic neuropathy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with ≥ 50% improvement of pain at 12 weeks or less5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Duloxetine 20 mg daily
1213Risk Ratio (M-H, Random, 95% CI)1.43 [0.98, 2.09]

    1.2 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Random, 95% CI)1.91 [1.26, 2.87]

    1.3 Duloxetine 60 mg daily
4908Risk Ratio (M-H, Random, 95% CI)1.73 [1.44, 2.08]

    1.4 Duloxetine 120 mg daily
4870Risk Ratio (M-H, Random, 95% CI)1.46 [1.08, 1.97]

    1.5 All doses
51655Risk Ratio (M-H, Random, 95% CI)1.53 [1.21, 1.92]

 2 Mean improvement in pain at 12 weeks or less5Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 Duloxetine 20 mg daily
1179Mean Difference (IV, Fixed, 95% CI)-0.45 [-1.05, 0.15]

    2.2 Duloxetine 60 mg daily
4722Mean Difference (IV, Fixed, 95% CI)-0.96 [-1.26, -0.65]

    2.3 Duloxetine 120 mg daily
4828Mean Difference (IV, Fixed, 95% CI)-0.93 [-1.21, -0.65]

 3 Number of participants with ≥ 30% improvement in pain at 12 weeks or less5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.18, 2.07]

    3.2 Duloxetine 60 mg daily
4799Risk Ratio (M-H, Fixed, 95% CI)1.53 [1.33, 1.75]

    3.3 Duloxetine 120 mg daily
3659Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.21, 1.58]

    3.4 All doses
41220Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.30, 1.63]

 4 Mean improvement in SF-36 Physical Subscore at 12 weeks or less3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Duloxetine 20 mg daily
1200Mean Difference (IV, Random, 95% CI)-0.27 [-2.42, 1.88]

    4.2 Duloxetine 60 mg daily
3514Mean Difference (IV, Random, 95% CI)2.65 [1.38, 3.92]

    4.3 Duloxetine 120 mg daily
2409Mean Difference (IV, Random, 95% CI)2.80 [1.04, 4.55]

 5 Mean improvement in SF-36 Mental Subscore at 12 weeks or less3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Duloxetine 20 mg daily
1200Mean Difference (IV, Fixed, 95% CI)1.11 [-0.98, 3.20]

    5.2 Duloxetine 60 mg daily
3514Mean Difference (IV, Fixed, 95% CI)1.08 [-0.32, 2.48]

    5.3 Duloxetine 120 mg daily
2409Mean Difference (IV, Fixed, 95% CI)2.23 [0.69, 3.77]

 6 Mean improvement in SF-36 Bodily Pain Subscore at 12 weeks or less2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Duloxetine 20 mg daily
1209Mean Difference (IV, Fixed, 95% CI)2.90 [-2.37, 8.17]

    6.2 Duloxetine 60 mg daily
2421Mean Difference (IV, Fixed, 95% CI)5.58 [1.74, 9.42]

    6.3 Duloxetine 120 mg daily
2420Mean Difference (IV, Fixed, 95% CI)8.19 [4.33, 12.05]

 7 Mean improvement in Patient Reported Global Impression of Improvement at 12 weeks or less6Mean Difference (IV, Random, 95% CI)Subtotals only

    7.1 Duloxetine 20 mg daily
1219Mean Difference (IV, Random, 95% CI)-0.23 [-0.56, 0.10]

    7.2 Duloxetine 40 mg daily
1252Mean Difference (IV, Random, 95% CI)-0.65 [-1.01, -0.29]

    7.3 Duloxetine 60 mg daily
51018Mean Difference (IV, Random, 95% CI)-0.60 [-0.77, -0.44]

    7.4 Duloxetine 120 mg daily
4870Mean Difference (IV, Random, 95% CI)-0.54 [-0.73, -0.35]

 8 Mean improvement in BPI Severity - average pain at 12 weeks or less2Mean Difference (IV, Random, 95% CI)Subtotals only

    8.1 Duloxetine 60 mg daily
2433Mean Difference (IV, Random, 95% CI)-0.97 [-1.38, -0.57]

    8.2 Duloxetine 120 mg daily
2428Mean Difference (IV, Random, 95% CI)-1.16 [-1.91, -0.41]

 9 Mean improvement in pain at rest (night pain) at 12 weeks or less3Mean Difference (IV, Random, 95% CI)Subtotals only

    9.1 Duloxetine 20 mg daily
1222Mean Difference (IV, Random, 95% CI)-0.28 [-0.90, 0.34]

    9.2 Duloxetine 60 mg daily
3664Mean Difference (IV, Random, 95% CI)-0.92 [-1.27, -0.57]

    9.3 Duloxetine 120 mg daily
3664Mean Difference (IV, Random, 95% CI)-1.10 [-1.45, -0.75]

 
Comparison 2. Duloxetine versus pregabalin in the treatment of painful diabetic neuropathy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with ≥ 50% improvement in pain at 12 weeks or less1804Risk Ratio (M-H, Fixed, 95% CI)1.46 [1.19, 1.80]

 2 Mean improvement in pain at 12 weeks or less1804Mean Difference (IV, Fixed, 95% CI)-0.62 [-0.92, -0.32]

 3 Number improved ≥ 30% at 12 weeks or less1804Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.20, 1.68]

 
Comparison 3. Duloxetine versus placebo in the treatment of fibromyalgia

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with ≥ 50% improvement of pain at 12 weeks or less5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Duloxetine 20 mg daily
1223Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.91, 2.14]

    1.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.75, 1.35]

    1.3 Duloxetine 60 mg daily
2528Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.20, 2.06]

    1.4 Duloxetine 120 mg daily
41234Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.40, 2.03]

    1.5 All doses
51887Risk Ratio (M-H, Fixed, 95% CI)1.50 [1.29, 1.75]

 2 Number of participants with ≥ 50% improvement of pain at more than 12 weeks2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Duloxetine 60 mg daily
1373Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.10, 2.27]

    2.2 Duloxetine 120 mg daily
2616Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.07, 1.79]

    2.3 Duloxetine all doses
2845Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.09, 1.79]

 3 Number of participants with ≥ 30% improvement of pain at 12 weeks or less4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Duloxetine 20 mg daily
1223Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.94, 1.79]

    3.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.89, 1.45]

    3.3 Duloxetine 60 mg daily
2528Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.24, 1.85]

    3.4 Duloxetine 120 mg daily
31020Risk Ratio (M-H, Fixed, 95% CI)1.46 [1.26, 1.69]

    3.5 All doses
41673Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.22, 1.56]

 4 Mean improvement in pain at 12 weeks or less2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 Duloxetine 30 mg daily
1308Mean Difference (IV, Fixed, 95% CI)-0.31 [-0.86, 0.24]

    4.2 Duloxetine 120 mg daily
1507Mean Difference (IV, Fixed, 95% CI)-0.80 [-1.35, -0.25]

 5 Mean improvement in the SF-36 mental component summary subscore6Mean Difference (IV, Random, 95% CI)Subtotals only

    5.1 Duloxetine 20 mg daily
1223Mean Difference (IV, Random, 95% CI)0.81 [-2.37, 3.99]

    5.2 Duloxetine 30 mg daily
1308Mean Difference (IV, Random, 95% CI)2.69 [0.31, 5.07]

    5.3 Duloxetine 60 mg daily
2515Mean Difference (IV, Random, 95% CI)3.31 [0.59, 6.02]

    5.4 Duloxetine 120 mg daily
51531Mean Difference (IV, Random, 95% CI)4.22 [2.43, 6.02]

 6 Mean improvement in the SF-36 physical component summary subscore6Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Duloxetine 20 mg daily
1223Mean Difference (IV, Fixed, 95% CI)0.81 [-1.92, 3.54]

    6.2 Duloxetine 30 mg daily
1308Mean Difference (IV, Fixed, 95% CI)0.84 [-1.17, 2.85]

    6.3 Duloxetine 60 mg daily
2515Mean Difference (IV, Fixed, 95% CI)1.28 [-0.33, 2.89]

    6.4 Duloxetine 120 mg daily
51531Mean Difference (IV, Fixed, 95% CI)2.13 [0.95, 3.30]

 7 Mean improvement in the SF-36 Bodily Pain Subscore4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 Duloxetine 60 mg daily
1221Mean Difference (IV, Fixed, 95% CI)8.2 [3.20, 13.20]

    7.2 Duloxetine 120 mg daily
41243Mean Difference (IV, Fixed, 95% CI)5.96 [3.76, 8.16]

 8 Mean improvement in the Patient reported Global Impression of Change at completion of trial4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 Duloxetine 20 mg daily
1223Mean Difference (IV, Fixed, 95% CI)-0.54 [-0.96, -0.12]

    8.2 Duloxetine 30 mg daily
1308Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.71, -0.05]

    8.3 Duloxetine 60 mg daily
2519Mean Difference (IV, Fixed, 95% CI)-0.45 [-0.73, -0.18]

    8.4 Duloxetine 120 mg daily
3826Mean Difference (IV, Fixed, 95% CI)-0.44 [-0.66, -0.23]

 
Comparison 4. Duloxetine versus placebo for the treatment of pain in major depressive disorder

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with > 50% pain relief at 12 weeks or less21023Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.19, 1.59]

 2 Participants with > 30% pain relief at 12 weeks or less31359Risk Ratio (M-H, Fixed, 95% CI)1.27 [1.15, 1.40]

 3 Mean improvement in pain at 12 weeks or less31359Mean Difference (IV, Fixed, 95% CI)-0.55 [-0.75, -0.35]

 
Comparison 5. Duloxetine versus placebo in the treatment of central neuropathic pain

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean improvement in pain at 12 weeks or less148Mean Difference (IV, Fixed, 95% CI)-1.0 [-2.05, 0.05]

 2 Mean improvement in SF-36 Physical Subscore148Mean Difference (IV, Fixed, 95% CI)2.0 [-12.72, 16.72]

 3 Mean improvement in the SF-36 Mental Subscore at 12 weeks148Mean Difference (IV, Fixed, 95% CI)4.0 [-6.75, 14.75]

 4 Mean improvement in the SF-36 Bodily Pain Subscore148Mean Difference (IV, Fixed, 95% CI)8.0 [-0.81, 16.81]

 5 Number of participants improved on PGI-I (better or very much better)148Risk Ratio (M-H, Fixed, 95% CI)2.75 [1.02, 7.44]

 
Comparison 6. Duloxetine versus placebo: adverse events during first 12 weeks of treatment for painful neuropathy or fibromyalgia

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Proportion of participants with any adverse event14Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.03, 1.52]

    1.2 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.01, 1.31]

    1.3 Duloxetine 60 mg daily
134521Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.10, 1.20]

    1.4 Duloxetine 120 mg daily
3688Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.09, 1.30]

    1.5 Duloxetine all doses
145258Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.11, 1.20]

 2 Nausea13Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Duloxetine 20 mg daily
1230Risk Ratio (M-H, Random, 95% CI)1.45 [0.71, 3.00]

    2.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Random, 95% CI)5.43 [2.34, 12.58]

    2.3 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Random, 95% CI)6.55 [1.85, 23.17]

    2.4 Duloxetine 60 mg daily
113642Risk Ratio (M-H, Random, 95% CI)2.61 [2.14, 3.18]

    2.5 Duloxetine 120 mg daily
4787Risk Ratio (M-H, Random, 95% CI)2.89 [2.06, 4.04]

 3 Dry mouth7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Duloxetine 20 mg daily
1230Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.30, 2.47]

   3.2 Duloxetine 40 mg daily
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Duloxetine 60 mg daily
62004Risk Ratio (M-H, Fixed, 95% CI)2.63 [1.89, 3.67]

    3.4 Duloxetine 120 mg daily
3567Risk Ratio (M-H, Fixed, 95% CI)3.40 [1.94, 5.96]

 4 Dizziness9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Duloxetine 20 mg daily
1230Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.33, 2.33]

    4.2 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)5.89 [1.22, 28.58]

    4.3 Duloxetine 60 mg daily
82257Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.35, 2.51]

    4.4 Duloxetine 120 mg daily
4787Risk Ratio (M-H, Fixed, 95% CI)2.44 [1.55, 3.83]

 5 Somnolence10Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Duloxetine 20 mg daily
1230Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.41, 2.43]

    5.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)2.22 [0.70, 7.06]

    5.3 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.15, 4.38]

    5.4 Duloxetine 60 mg daily
82678Risk Ratio (M-H, Fixed, 95% CI)2.94 [2.17, 3.97]

    5.5 Duloxetine 120 mg daily
4787Risk Ratio (M-H, Fixed, 95% CI)4.76 [2.93, 7.74]

 6 Adverse event leading to cessation17Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Duloxetine 20 mg daily
2453Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.78, 2.39]

    6.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)1.54 [0.69, 3.44]

    6.3 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)1.96 [0.81, 4.77]

    6.4 Duloxetine 60 mg daily
144837Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.60, 2.37]

    6.5 Duloxetine 120 mg daily
71462Risk Ratio (M-H, Fixed, 95% CI)2.30 [1.74, 3.04]

    6.6 All doses
176285Risk Ratio (M-H, Fixed, 95% CI)1.99 [1.67, 2.37]

 7 Serious adverse event16Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   7.1 Duloxetine 20 mg daily
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 Duloxetine 30 mg daily
1308Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.02]

    7.3 Duloxetine 40 mg daily
1252Risk Ratio (M-H, Fixed, 95% CI)2.95 [0.50, 17.30]

    7.4 Duloxetine 60 mg daily
144842Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.60, 1.32]

    7.5 Duloxetine 120 mg daily
61257Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.25, 1.35]

    7.6 All doses
144976Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.53, 1.25]

 
Summary of findings for the main comparison. Duloxetine for the treatment of painful diabetic neuropathy

Duloxetine for painful diabetic neuropathy

Patient or population: patients with painful neuropathy or chronic pain from diabetic peripheral neuropathy
Settings: primary and secondary care
Intervention: duloxetine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDuloxetine

Number of patients with ≥ 50% improvement of pain at 12 weeks or less

Duloxetine 60 mg daily
11-point Likert score

Follow-up: 8 to 12 weeks
257 per 1000445 per 1000
(370 to 535)
RR 1.73
(1.44 to 2.08)
908
(4 studies)
⊕⊕⊕⊝
moderate1
NNTB for ≥ 50% reduction in pain at 60 mg daily: 5 (95% CI 4 to 7)

Mean improvement in pain at 12 weeks or less

Duloxetine 60 mg daily
11-point Likert score

Scale from: 0 to 10
Follow-up: 8 to 12 weeks
The mean mean improvement in pain at 12 weeks or less - duloxetine 60 mg daily in the control groups was
-1.65 units
The mean mean improvement in pain at 12 weeks or less - duloxetine 60 mg daily in the intervention groups was
0.96 lower
(1.26 to 0.65 lower)
-722
(4 studies)
⊕⊕⊕⊝
moderate2

Number of patients with ≥ 30% improvement in pain at 12 weeks or less

Duloxetine 60 mg daily
11-point Likert scale

Follow-up: 8 to 12 weeks
411 per 1000629 per 1000
(547 to 719)
RR 1.53
(1.33 to 1.75)
799
(4 studies)
⊕⊕⊕⊝
moderate1
NNTB for ≥ 30% reduction in pain at 60 mg duloxetine daily: 5 (95% CI 3 to 7)

Mean improvement in Patient Reported Global Impression of Change at 12 weeks or less

Duloxetine 60 mg daily
VAS

Scale from: 0 to 10
Follow-up: 8 to 12 weeks
The mean mean improvement in patient reported global impression of improvement change at 12 weeks or less - duloxetine 60 mg daily in the control groups was
-3.06 units
The mean mean improvement in Patient Reported Global Impression of Improvement Change at 12 weeks or less - duloxetine 60 mg daily in the intervention groups was
0.6 lower
(0.77 to 0.44 lower)
-1018
(5 studies)
⊕⊕⊕⊝
moderate3

Adverse event leading to cessation

All neuropathic pain indications

Duloxetine 60 mg daily
56 per 1000109 per 1000
(90 to 133)
RR 1.95
(1.6 to 2.37)
4837
(14 studies)
⊕⊕⊝⊝
low4
NNTH for duloxetine 60 mg daily, all indications, and all adverse effects leading to cessation: 18 (95% CI 13 to 30)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Four trials, all company sponsored and performed but all trials pre-registered on ClinicalTrials.gov have been published. No publication bias detected.
2 Two of four studies by company. Effect in Rowbotham nonsignificant, contributing some heterogeneity.
3 Five studies but wide CIs in the independent studies.
4 Variable quality of adverse event collection.
 
Summary of findings 2. Duloxetine for the treatment of the chronic pain of fibromyalgia

Duloxetine for the chronic pain of fibromyalgia


Patient or population: patients with the chronic pain of fibromyalgia
Settings:
Intervention: duloxetine


OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments


Assumed riskCorresponding risk

ControlDuloxetine

Number with ≥ 50% improvement of pain at 12 weeks or less

Duloxetine 60 mg daily
11-point Likert scale
Follow-up: 8 to 12 weeks
233 per 1000366 per 1000
(280 to 480)
RR 1.57
(1.2 to 2.06)
528
(2 studies)
⊕⊕⊝⊝
low1,2
NNTB for ≥ 50% improvement of pain at duloxetine 60 mg daily: 8 (95% CI 4 to 21)

Number with ≥ 30% improvement of pain at 12 weeks or less

Duloxetine 60 mg daily

Follow-up: 8 to 12 weeks
347 per 1000527 per 1000
(430 to 642)
RR 1.52
(1.24 to 1.85)
528
(2 studies)
⊕⊕⊝⊝
low1,2
NNTB for ≥ 30% improvement of pain at duloxetine 60 mg daily: NNT 6 (95% CI 3 to 12)

Mean improvement in the Patient Reported Global Impression of Change at completion of trial

Duloxetine 60 mg daily
VAS

Scale from: 0 to 10
Follow-up: 12 weeks
The mean mean improvement in the patient reported global impression of change at completion of trial - duloxetine 60 mg daily in the control groups was
3.52 units
The mean mean improvement in the patient reported global impression of change at completion of trial - duloxetine 60 mg daily in the intervention groups was
0.45 lower
(0.73 to 0.18 lower)
-519
(2 studies)
⊕⊕⊝⊝
low1,2

Mean improvement in pain at 12 weeks or less

Duloxetine 120 mg daily

LikertScale from: 0 to 10
Follow-up: 12 weeks
The mean mean improvement in pain at 12 weeks or less - duloxetine 120 mg daily in the control groups was
-1.5
The mean mean improvement in pain at 12 weeks or less - duloxetine 120 mg daily in the intervention groups was
0.8 lower
(1.35 to 0.25 lower)
-507
(1 study)
⊕⊕⊕⊝
moderate1

Adverse eventsSee commentSee commentSee comment-See commentSee pooled adverse events in 'Summary of findings' table 1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome


GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Substantial dropouts from all trials inform the outcomes.
2 Mostly female in some trials, all female in others.
 
Summary of findings 3. Duloxetine for the treatment of pain in major depressive disorder

Duloxetine for pain in major depressive disorder

Patient or population: patients with pain in major depressive disorder
Settings:
Intervention: duloxetine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDuloxetine

Number with ≥ 50% pain relief at 12 weeks or less
Follow-up: 12 weeks
360 per 1000493 per 1000
(428 to 572)
RR 1.37
(1.19 to 1.59)
1023
(2 studies)
⊕⊕⊕⊝
moderate1
NNTB for ≥ 50% pain relief at < 12 weeks 60 mg duloxetine daily: 8 (95% CI 5 to 14)

Number with ≥ 30% pain relief at 12 weeks or less467 per 1000593 per 1000
(537 to 654)
RR 1.27
(1.15 to 1.4)
1359
(3 studies)
⊕⊕⊝⊝
low1,2
NNTB for ≥ 30% pain relief at < 12 weeks 60 mg duloxetine: 8 (95% CI 4- to 14)

Mean improvement in pain at 12 weeks or less
Visual analogue scale. Scale from: 0 to 10.
Follow-up: 12 weeks
The mean mean improvement in pain at 12 weeks or less in the control groups was
1.23
The mean mean improvement in pain at 12 weeks or less in the intervention groups was
0.55 lower
(0.75 to 0.35 lower)
1359
(3 studies)
⊕⊕⊝⊝
low1,2

Mean improvement in Patient Reported Global Impression of Change at 12 weeks or lessSee commentSee commentNot estimable-See commentOutcome not measured

Adverse eventsSee commentSee commentNot estimable-See commentSee pooled adverse events in 'Summary of findings' table 1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Mixed causes for pain, not necessarily neuropathic.
2 Substantial dropouts partially accounted for by last observation carried forward and statistical manipulation.