Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments / limitations

GABAPENTIN VS PLACEBO

Levendoglu, 2004

Type of study:

Randomized crossover study

Country:

Turkey

Source of funding:

No funds were received in support of this work. No benefits in any

form have been or will be received from a commercial party related

directly or indirectly to the subject of this manuscript.

Inclusion criteria:

Paraplegic patients with complete traumatic SCI at the thoracic and lumbar level, aged between 20 and 65 years, with neuropathic pain (NP) for more than 6 months confirmed by a physician. A score above 4 on the 11-point Neuropathic Pain Scale (0–10), representing moderate to severe pain, was required for the study.

Exclusion criteria:

Severe cognitive impairment, pregnancy, seizure disorder, the use of anticonvulsants and antidepressants, major depression or a score above 16 on the Beck Depression Inventory, and hypersensitivity to GBP. Concurrent analgesic medications were not allowed at least 15 days before and during the study.

N total at baseline:

N=20

Important prognostic factors²:

Baseline scores of VAS, Neuropathic Pain Scale (NPS), and Lattinen test (LQ) both at the beginning

of the study and at the end of washout period were similar (P>0.05).

Intervention:

Gabapentin (GBP)(N=20)

Treatment regimen:

The patients were randomized into initially GBP treated group (group A) or an initially placebo control treatment group (group B) with equal numbers. Both GBP and placebo were provided as identically appearing capsules. During the first 4 weeks of the study, patients received gradually titrated dosages of GBP/placebo administered orally 3 times a day. Total dose at the end of each week was: week 1, 900 mg/day; week 2, 1800 mg/day; week 3, 2400 mg/day; and week 4, 3600 mg/day. Before increasing the dose at each interval, the subject was seen by

a blinded physician to document any adverse side effects. If no

significant side effects were noted, the increase of dose was made.

The trial lasted 18 weeks in total. This period included a 4-week medication/placebo titration period, during which maximum dose was reached for each subject. This was followed by a 4-week stable dosing period when the patients continued to receive maximum tolerated doses, a 2-week washout period, then a crossover of 4 weeks of medication /placebo titration, and another 4 weeks of stable dosing period. Patients were hospitalized during titration periods.

Control intervention:

Placebo (N=20)

Length of follow-up:

18 weeks

Loss-to-follow-up:

0/20=0%

Outcome measures and effect sizes

Neuropathic pain scale (NPS)

0-10 point scale. Score > 4 represents moderate to severe pain.

Visual Analogue Scale (VAS)

ranged from 0 (no pain) to 100 (worst pain imaginable)

Change in NPS (from baseline to 8 weeks)

Mean (SD)

Gabapentin:

52.8 (13.0) to 61.9 (14.3) for parameters pain intensity, sharp, hot, unpleasantness, deep pain, and surface pain. Pain reduction statistically significant (p<0.05)

Placebo:

7.8 (7.7) to 13.2 (4.8) for parameters pain intensity, sharp, hot, unpleasantness, deep pain, and surface pain. Pain reduction statistically significant (p<0.05).

GBP treatment ensured more relief for these descriptors of NP compared to placebo, which was statistically significant (p<0.05).

Both placebo and GBP did not

affect NPS scores for cold, itchy, sensitive, and dull varieties of NP (P>0.05).

Change in VAS (from baseline to 8 weeks) 

Mean (SD)

Gabapentin: 60.7% (12.7)

Placebo: 10.3%  (2.8)

Difference between groups statistically significant (p<0.000).

Adverse effects (AE)

GBP: n=17/20=85% patients had AE

Placebo: n=6/20=30% patients had AE.

Difference between groups statistically significant (p<0.05).

Most frequently reported AEs:

weakness, oedema, vertigo, sedation, headache, itching.

These side effects did not lead to discontinuation of treatment.

One patient in placebo group and four patients in GBP group had more than one side effect.

The mean dose of GBP without side effects was 2235 ± 500.8 mg/day (900–2700), and the mean maximum tolerated

dose was 2850.0 ± 750.7 mg/day (1200–3600).

Small sample size (N=20)

Unclear if patients had at- or below-level NP.

Concurrent analgesic medications were not allowed at least 15 days before and during the study.

Tai, 2002

Type of study:

Randomized crossover study

Country:

USA

Source of funding:

Study supported by American Academy of Physical Medicine and Rehabilitation and clinical SCI grant from Eastern Paralyzed Veterans Association.

Inclusion criteria:

Patients with traumatic SCI > 30 days, aged between 18 and 85 years, with neuropathic pain confirmed by a physician. A score >  4 on the 11-point Neuropathic Pain Scale (0–10), representing moderate to severe pain, was required for the study.

Exclusion criteria:

Severe cognitive impairment, pregnancy, seizure disorder, the use of anticonvulsants and antidepressants, major depression or a score > 16 on the Beck Depression Inventory, hypersensitivity to GBP, renal insufficiency with a creatinine clearance < 60 mL/minute

N total at baseline:

N=14

Important prognostic factors²:

Not reported

Intervention:

Gabapentin (GBP)(N=7)

Treatment regimen:

The patients were randomized into initially GBP treated group (group A) or an initially placebo control treatment group (group B). Both GBP and placebo were provided as identically appearing capsules.  Concurrent medications, including anticonvulsant, antidepressants,  and other analgesic medications, were continued during study if already taking these medications. In addition, subjects experiencing pain were allowed to use additional analgesics (i.e. nonsteroidal anti-inflammatory, tricyclic anti-depressants, and narcotics) on as-needed basis. Study lasted in total 10 weeks, including 4 weeks of progressively increasing medication/placebo treatment, a 2-week washout period, then a crossover of 4 weeks of medication/placebo treatment.

Initial dosage of 300 mg/day GBP for 2 days. After 2 days, dosage was increased to a total of dose of 600 mg/day for next 5 days, followed by incremental increases in total daily dosage to 900 mg (day 8), 1200 mg (day 15) and 1800 mg (day 22). Before increasing the dose at each interval, the subject was seen by a blinded physician to document any adverse side effects. If no

significant side effects were noted, the increase of dose was made.

Control intervention:

Placebo (N=7)

Length of follow-up:

10 weeks

Loss-to-follow-up:

7/14=50%

N=1 side effect,

N=2 medical complications not related to study

N=4 lack of compliance (withdrew secondary to long duration of study).

Outcome measures and effect sizes

Change in NPS (from baseline to 4 weeks)

There was a significant decrease of ‘unpleasant feeling’ by fourth week of GBP (p=0.028). No significant difference was noted in other pain descriptors of NPS between GPB and placebo.

No means or other statistical data reported.

Adverse effects

N=1 side effect (urinary retention). Not reported during which treatment. 

Small sample size (N=14)

High loss to follow-up (50%). No ITT analysis.

Unclear if patients had at- or below-level NP.

Concurrent analgesic medications were continued during study and additional analgesics were given on as- needed basis. No statistical analysis to adjust for co-medication.

Clinically relevant difference (≥20% pain reduction) not reported

PREGABALIN VS PLACEBO

Siddall, 2006

Type of study:

RCT

Country:

Australia (8 centres)

Source of funding:

Supported by Pfizer. Authors employee or received honorarium of Pfizer.

Inclusion criteria:

Men or women ≥18 years of age with a traumatic SCI (paraplegia or tetraplegia) that had been ≥1 year previously, in whom it had been nonprogressive ≥ 6 months. Patients had

central neuropathic pain as defined by the IASP classification. The pain must have been chronic, having persisted continuously ≥ 3 months or with relapses and remission ≥6 months, and started after sustaining the SCI. Central pain was diagnosed in most cases on the basis that the

pain was below the level of the neurologic lesion. All patients were required to have a score ≥40 mm on the 100 mm visual analogue scale (VAS) at both screening and randomization. To be

randomized, patients were also required to have completed a daily pain diary upon awakening in the week before treatment in which

pain in the last 24 hours was rated on an 11-point numerical rating scale (NRS) from 0=no pain to 10=worst possible pain,

and to have an average score ≥4 based on at least four daily entries.

Patients taking NSAIDs, opioid analgesics, non-opioid analgesics, AEDs, and antidepressant medications were allowed to enter if they had been stable ≥1 month before the study and would remain so during the study. Patients taking muscle relaxants were also allowed to enter. Those taking gabapentin were required to discontinue treatment ≥ 1 week before the study. Patients were required to be in generally sound medical and mental health.

Exclusion criteria:

Patients with severe pain of other origin that could confound the assessment of central neuropathic pain related to SCI. Those with a creatinine clearance <60 mL/minute were excluded, as were women who were breastfeeding or pregnant.

N total at baseline: 137

Important prognostic factors²:

Differences in types of concomitant pain medication between groups at baseline, e.g.: opioids: 47.8% placebo vs. 30% pregabalin; tricyclic antidepressants: 17.9% placebo vs. 32.9% pregabalin; NSAIDs/COX-2: 28.3% placebo vs 18.6% pregabalin; muscle relaxants: 37.3% placebo vs 54.3% pregablin

Intervention:

Pregabalin (N=70)

Treatment regimen:

Patients were randomized to either flexible dose pregabalin 150 to

600 mg/day or placebo taken twice daily (BID) for 12 weeks. Study medication (or matching placebo capsules) was initiated at 150 mg/day for the first week and was then increased to 300 mg/day. The dose could be further increased to 600 mg/day after the second week if needed for efficacy. The dose could be reduced from 300 mg/day to 150 mg/day at the end of the second week if the higher dose was

not well tolerated. In patients escalated to 600 mg/day, the dose

could be reduced to 300 mg/day at the end of the third week if this

dose was not well tolerated. No subsequent changes in dose were

permitted during the remainder of the study.

Control intervention:

Placebo (N=67)

Treatment regimen:

See under Intervention

Length of follow-up:

12 weeks

Loss-to-follow-up:

Pregabalin:

21/70=30%

Withdrawn because of: adverse events (15), lack of efficacy (5), other (1)

Placebo:

30/67=45%

Withdrawn because of: adverse events (9), lack of efficacy (20), other (1)

Intention-to-treat (ITT) analysis included 136 patients (N=69 pregabalin and N=67 placebo) who took at least one dose of study medication and had at least one post-baseline assessment.

One patient on pregabalin was not included in the ITT analysis of

efficacy because there was no on-treatment efficacy assessment.

ITT analysis based on last observation carried forward (LOCF) for patients who did not complete study. This may introduce bias as it assumes that dropout is not related to variables such as group assignment or side effects.

Outcome measures and effect sizes

Primary outcome measure

Endpoint mean pain score at 12 weeks. Pain rated on an 11-point numerical rating scale (NRS) from 0=no pain to 10=worst possible pain.

Analysis of covariance for endpoint comparison between groups controlling for  study center and baseline values.

Secondary outcome measures

% of patients with ≥ 30% pain reduction

Change in pain score (from baseline to 12 weeks)

Mean (SD)

Pregabalin (N=69)

Baseline: 6.54 (1.3)

Endpoint: 4.62 (2.1)

Change: 1.92

Placebo (N=67):

Baseline: 6.73 (1.4)

Endpoint: 6.27 (2.1)

Change: 0.46

Mean difference between groups:

1.53 (95%CI: 0.92-2.15), p<0.001

The mean difference (95% CI) in the endpoint pain scores be-

tween the placebo and pregabalin groups according to concomitant pain medications were as follows: taking any

pain medication=1.48 (0.8, 2.2; p<0.001), not taking any

pain medication=1.87 (0.7, 3.0; p<0.01), taking TCAs=2.64 (0.9, 4.4; p<0.01), not taking TCAs=1.21 (0.5, 1.9;

p<0.001), taking opioids=2.42 (1.3, 3.5; p<0.01), and

not taking opioids 1.29 (0.5, 2.1; p<0.01). The differences

between those taking and not taking any pain medications,

TCAs, and opioids were not significant.

% of patients with ≥ 30% pain reduction

Pregabalin: 42%

Placebo: 16%

P=0.001

Adverse events (AE)

Treatment-emergent AE (e.g. somnolence, dizziness, edema, dry mouth)

Pregabalin: 96%

Placebo: 75%

Discontinuations due to AE

Pregabalin: 21%

Placebo: 13%

High percentage of withdrawals (30% in pregabalin group and 45% in placebo group). LCOF method not adequate.

Concomitant pain medication allowed during the study. Analysis taking co-medication into account showed that the differences between those taking and not taking any pain medications, TCAs, and opioids were not significant.

Possible publication bias (study was sponsored, conducted and written by Pfizer).

Cardenas,

2013

Type of study:

RCT

Country:

Chile, China, Columbia, the Czech Republic, Hong Kong, India, Japan, the Philippines, the Russian Federation, and the United States

Source of funding:

Sponsored by Pfizer. Authors employee of or stocks in Pfizer

Inclusion criteria:

Patients aged ≥ 18 years with C2-T12 SCI, complete or incomplete, of ≥ 12 months’ duration were recruited through physician database and peer referral from 2007 to 2011 at 60 medical centers in Chile, China, Columbia, the Czech Republic, Hong Kong, India, Japan, the Philippines, the Russian Federation, and the United States. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. Patients were required to have below-level neuropathic pain (type 14 or 15 according to Bryce-Ragnarsson taxonomy) continuously for ≥ 3 months or remitting/relapsing for ≥ 6 months. Patients with SCI due to trauma, diving, ischemia, or surgery to remove benign tumors were included. An average pain score of ≥ 4, on an 11-point scale, in the week before randomization was also required.

Exclusion criteria:

the presence of other neurologic disorders, medical conditions,

or pain that could confound the assessment of neuropathic pain

associated with SCI; previous participation in a trial of, or intolerance to, pregabalin; intolerance to gabapentin; preexisting myelopathy of other causes; traumatic SCI superimposed on congenital canal stenosis; and retinal abnormalities or previous treatment with retinotoxic agents.

N total at baseline:

220

Important prognostic factors²:

Differences in types of concomitant pain medication between groups at baseline, e.g.: opioids: 30.5% placebo vs. 20.5% pregabalin; TCA/SNRI: 15.9% placebo vs. 8.9% pregabalin; benzodiazepine: 30.8% placebo vs 20.5 pregabalin

Intervention:

Pregabalin (N=112)

Treatment regimen

The study comprised a 4-week dose-optimization period, a 12-week dose-maintenance period, and a 1-week taper period. Patients received twice-daily pregabalin initially 150 mg/d for 7 days. Based on tolerability, the dose of pregabalin was increased to 300 mg/d on day 8, 450 mg/d on day 15, and 600 mg/d on day 22. After day 8, weekly dose adjustments were allowed until the end of the optimization period (day 29).

During the 12-week maintenance period that followed, patients received their optimized dose of pregabalin with 1 single-level dose reduction allowed. Patients were tapered off of pregabalin over a 1-week period. Patients were required to discontinue gabapentin or cannabinoids at least 7 days before screening, and pregabalin at least 60 days prior. Non-steroidal anti-inflammatory drugs, cyclo-oxygenase-2 inhibitors, and acetaminophen (≤1.5 g/d in Japan, ≤4 g/d in all other countries) were permitted as rescue therapy. Antidepressants were permitted if

the patient was on a stable dose within 30 days before the first visit.

Control intervention:

Placebo (N=108)

Treatment regimen

Patients received matching placebo (1:1

ratio).

Length of follow-up:

16 weeks

Loss-to-follow-up:

Pregabalin: 19/112=17%

8 adverse event, 5 protocol violation, 3 withdrew, 1 lack of efficacy , 2 other

Placebo:

17/108=16%

1 did not receive intervention, 8 adverse event, 3 protocol violation, 3 withdrew, 2 lack of efficacy

All efficacy analyses, unless noted otherwise, were based on the modified intent-to-treat population, which included all patients who took at least 1 dose of study medication and excluded 8 patients who were randomized before the protocol was amended on February 12, 2008.

This amendment was designed to reduce dropouts and sustain

efficacy and tolerability throughout the study. This resulted in a 4-week flexible-dose adjustment phase (revised from a 2-week

dose-escalation phase), followed by a 12-week dose-maintenance

phase with 1 permissible dose reduction (revised from a 12-week fixed-dose phase). Thus, the duration of double-blind treatment from randomization to end of taper increased from 15 to 17 weeks, and the number of treatment arms decreased from 4 to 2.The safety

population included every patient who received at least 1 dose of study medication and at least 1 safety assessment.

Total in modified ITT analysis:

N=106 pregabalin

N=105 placebo

Not in analysis:

Pregabalin: 3/108=3%

1 did not receive intervention, 2 were randomized before the protocol was amended on Feb 12,

2008

Placebo: 6/112=5%

6 were randomized before the protocol was amended on Feb 12, 2008.

Outcome measures and effect sizes

Primary outcome measure

Duration-adjusted average change (DAAC) in pain. DAAC is a

weighted average, proportional to participation duration, of observed and unobserved (missing) pain scores. Pain scores were derived from diaries, in which patients rated the intensity of their SCI-associated pain during the previous 24 hours on an 11-point scale from 0=no pain to 10=worst possible pain.

Secondary outcome measures

% of patients with ≥ 30% pain reduction

End point refers to week 16 (before the 1-week taper period), or early termination.

Analysis comparing between treatment groups used ANOVA model including treatment, baseline pain score, baseline Pain Catastrophizing Scale total score, and pooled center as covariates.

Duration-adjusted average change (DAAC) in pain 

Mean (SE)

Pregabalin: -1.66 (0.16) (N=105)

Placebo: -1.07 (0.15) (N=106)

Difference: -0.59 (0.20),  95%CI: -0.98 to -0.20, p=0.003

% of patients with ≥ 30% pain reduction

Pregabalin: 42%

Placebo: 16%

P=0.001

Adverse events (AE)

N (%)

Patients with ≥1 AE:

Pregabalin: 75 (67%) (N=112)

Placebo: 50 (47%) (N=107)

e.g. somnolence, dizziness, peripheral edema, dry mouth

Discontinuations due to AE

Pregabalin: 6 (5.4%) (N=112)

Placebo: 5 (4.7%) (N=107)

Study builds on the previous study (Siddall, 2006) by including a broader (trau-

matic and nontraumatic SCI), larger (220 vs 137 patients), multinational patient population. Additionally, the current study includes a longer treatment duration (16 vs 12 weeks).

Possible publication bias (study was sponsored, conducted and written by Pfizer).

Mixed population (traumatic (84%) and non-traumatic SCI (16%). No separate analysis for only traumatic SCI.

Concomitant pain medication allowed during the study.

GABAPENTIN VS PREGABALIN

Kaydok, 2014

Type of study:

Randomized crossover study

Country:

Turkey

Source of funding:

Not reported

Inclusion criteria:

Patients with neuropathic pain due to traumatic or non-traumatic spinal cord injury; patients with an average VAS pain score of 4 and above during the last week were included in the study; patients above 18 years old and below 70

years old; patients who previously did not or at present do not receive any of the drugs that will be used in the study.

Exclusion criteria:

Comorbid medical conditions

N total at baseline:

N=28

Important prognostic factors²:

The average age of the patients was 42.8 ±

12.3 years. The average length of time since the

spinal cord injury occurred was 35.3±28.8 months,

and average duration of neuropathic pain was

29.3±25.8 months. 14 patients (74%) were men, and 5 patients (26%) were women. Fifteen of the injuries were traumatic (79%), 3 were iatrogenic (16%) and one was related to myelitis (5%). Three of the patients were tetraplegic (16%), 16 (84%) were paraplegic.

Intervention A:

Gabapentin (N=28)

Treatment regimen:

Gabapentin (GP) was initiated to the patients at recommended

initial doses after the baseline evaluation: Day 1: 300 mg/day, Day 2: 600 mg/day, Day 3 to Day 7: 900 mg/day, at the end of 2nd

week: 1800 mg/day, at the end of 3rd week: 2700 mg/day, at the end of 4th week: the maximum dose of

3600 mg/day. The daily oral dose was given in three divided doses. The maximum doses were titrated in the first 4 weeks. The stable doses were used during the 4

weeks after titration. Total of 8 weeks follow-up (4 weeks titration and 4 weeks stable dose). Treatment groups were crossed over after 2 weeks of wash-out period to receive the other treatment for 8 weeks.

The average daily dose was 3078 ± 811 mg/day for gabapentin in the patients who completed the study.

Intervention B:

Pregabalin (N=28)

Treatment regimen:

Pregabalin (PG) was initiated to the patients at recommended initial doses after the baseline evaluation: for the first week 150 mg/day, for the second week 300 mg/day, for the third week 450 mg/day, for the fourth week the

maximum dose of 600 mg/day. The daily oral dose was given in two divided doses.

The maximum doses were titrated in the first 4 weeks. The stable doses were used during the 4 weeks after titration. Total of 8 weeks follow-up (4 weeks titration and 4 weeks stable dose). Treatment groups were crossed over after 2 weeks of wash-out period to receive the other treatment for 8 weeks.

The average daily dose was 434 ± 172 mg/day for pregabalin in the patients who completed the study.

Length of follow-up:

18 weeks

Loss-to-follow-up:

Gabapentin 3/24=12.5%

1 patient discontinued by own will, 2 patients due to side effects

Pregabalin: 6/25=24%

1 patient discontinued by own will, 5 patients due to side effects

One patient had to discontinue the study due to

the sudden, serious hemoptysis in gabapentin group;

and 1 patient had to discontinue the treatment due to

gastroesophageal reflux. One patient discontinued the study due to serious peripheral edema, two patients discontinued due to drowsiness and somnolence, one patient discontinued due to allergic rashes,

and one patient discontinued to the gait disturbance

in pregabalin group.

No intention-to-treat analysis; N=19 patients included in analysis

Outcome measures and effect sizes

Change in VAS pain score (between baseline and week 8) Mean (SD)

Gabapentin (N=25):

Baseline: 7.78 (1.27)

Endpoint: 3.57 (1.21)

Change: 4.21

Pregabalin (N=22):

Baseline: 8.05 (1.26)

Endpoint: 3.36 (1.11)

Change: 4.69

Improvement after 8 weeks in both groups statistically significant (p<0.001).

Mean difference between groups:

No statistically significant difference in improvement after 8 weeks between groups.

Neuropathic pain scale

Both gabapentin and

pregabalin did not affect NPS scores for cold, sensitive varieties of NP (p>0.05). All other types of NP decreased significantly with GBP/PRG at the fourth week compared to baseline and remained so at

eighth week (p<0.05).

No difference in effect was present between the two study groups (p>0.05).

Lattinen test

In LT parameters, no difference was present between the two study groups before or after the treatment (p>0.05).

Side effects (e.g. sedation, somnolence, edema)

Gabapentin: 16/24=67%

Pregabalin: 21/25=84%

No significant difference in the frequency of total side effects was found between treatment groups (p>0.05).

Small sample size (N=19 analysed)

Traumatic and non-traumatic SCI included (no separate analysis traumatic SCI)

Unclear if patients had at- or below-level NP.

Unclear if concomitant medication was allowed/used.

Clinically relevant difference in pain score not defined.

Yilmaz, 2015

Type of study:

Randomized crossover study

Country:

Turkey

Source of funding:

The authors declared that this study has received no financial support; No conflict of interest was declared by the

authors

Inclusion criteria:

SCI patients with pain below the level of injury in areas without normal sen-

sation, age between 14 and 75 years, and a Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (LANNS) score above 12.

Exclusion criteria:

concomitant brain injury, cognitive impairment, seizure disorder, the use of antiepileptics and antidepressants, and hypersensitivity history to gabapentin and pregabalin

N total at baseline:

30

Important prognostic factors²:

Baseline pain VAS : 7.05±1.92 (group A) vs 7.02±1.63 (group B)

Baseline BDI:

17.42±10.94 (group A) vs 10.64±5.31 (group B)

Baseline PDI:

18.50±16.44 (group A) vs 23.28±22.24 (group B)

Intervention A:

Gabapentin (N= 30)

Treatment regimen:

The 18-week study period included 8 weeks for gabapentin or pregabalin use and a 2-week washout period between the 2

medications. After the washout period, drugs were switched in

a crossover design. During the first 2 weeks of the use of each medicine, patients received gradually titrated dosages. Gabapentin was administered orally 3 times a day; however, pregabalin was administered 2 times a day. Before increasing the dose at each interval, the subject was observed by a blinded physician to document any side effects. If no significant side effects were noted, the dose was increased. Adverse effects of medicines were monitored and recorded. All patients’ dosages were titrated to tolerability up to 1800 mg/day for gabapentin and 300 mg/day for pregabalin during 2 weeks, regardless of any efficacy achieved at lower dosages.

Intervention B:

Pregabalin (N= 30)

Treatment regimen:

See under Intervention A

Length of follow-up:

18 weeks

Loss-to-follow-up:

Gabapentin: 4/30=13%

4 did not want to change medication while they were using first drug

Pregabalin: 5/30=17%

3 did not want to change medication while they were using first drug and 2 experienced the side effects of dizziness and nausea

No intention-to-treat analysis; N=21 patients included in analysis

Outcome measures and effect sizes

Change in pain score

Cross-over analysis of the results revealed that there was no statistically significant difference between gabapentin and pregabalin in terms of all assessments of neuropathic pain (pain and sleep VAS, Beck depression inventory, and the pain disability index) outcome measures (p>0.05)

Adverse effects

2/30=6.7% patients in the pregabalin group experienced side effects. These side effects led to discontinuation of treatment (dizziness and nausea).

Small sample size (N=21 analysed)

Results: overall (over both first and second period) change in pain scores not reported

Unclear if differences in baseline pain scores between groups were statistically significant.

Unclear if concomitant medication was allowed/used.

Clinically relevant difference in pain score not defined

LEVETIRACETAM VS PLACEBO

Finnerup, 2009

Type of study:

Randomized crossover study

Country:

Denmark

Source of funding:

This study was financially supported by

UCB Pharma, the Danish Medical Research Council

(no. 22040561) and Ludvig and Sara Elsass Foundation.

Inclusion criteria:

Patients aged ≥ 18 years with at- and/or below-level neuropathic pain for

at least 3 months due to trauma or disease of the spinal cord or cauda equina with a median pain intensity ≥ 4 on a 0–10

point numeric rating scale (NRS) during a 1-week baseline period.

Exclusion criteria:

known concomitant cerebral damage, pregnancy or lactation, alcohol or substance abuse, hypersensitivity to levetiracetam or pyrrolidine derivates,

epilepsy, psychiatric disease, depression, severe liver disease

or impaired renal function.

N total at baseline:

N=36

Important prognostic factors²:

Not reported

Intervention:

Levetiracetam (N=36)

Treatment regimen:

A 1-week baseline period was followed by two 5-week treatment periods with levetiracetam or identical placebo tablets, separated by a 1-week washout period. Tablets containing 500mg were administered as two divided doses.

The dose was gradually increased from 500mg x 2 in the first week to 1000mg x 2 in the second week and 1500mg x 2 in weeks 3–5. Patients were permitted to reduce the final dose to 2000 or 2500mg daily if they experienced unacceptable

adverse events, but the final dose had to be at least 2000mg and continued for at least 2 weeks to complete the trial. Paracetamol up to 6 tablets of 500mg daily was used as escape medication.

Patients taking antidepressants

were slowly tapered off during a prestudy period of at least 1 week before the baseline period. Concomitant treatment with spasmolytics (baclofen and tizanidine), gabapentin, pregabalin, opioids and simple analgesics (nonsteroid anti-inflammatory drugs, paracetamol or acetylsalicylic acid) for pain was allowed in a constant and unchanged dose during the trial.

Control intervention:

Placebo (N=36)

Length of follow-up:

12 weeks

Loss-to-follow-up:

Levetiracetam: 9/36=25%

7 adverse effects, 1 protocol violation, 1 accident with fracture

Placebo: 3/36=8.3%

2 adverse effects, 1 increased pain

24/36=67% included in analysis (achieved at least 2000mg per day for at least 2 weeks without

major protocol violation)

The withdrawn patients and the study population

did not differ in baseline characteristics, but there was a

tendency that withdrawn patients were more often treated with concomitant pain medications (11/12 versus 14/24, P=0.059).

Outcome measures and effect sizes

Primary outcome measure:

change in median daily pain intensity score (from 0 (no pain) to 10 (worst imaginable pain)) from the baseline week to the last week of treatment

Change in pain score (between baseline and week 5)

Median (range)

Levetiracetam (N=27):

Baseline: 6 (4-9)

Endpoint: 6 (3-9.5)

Placebo (N=33):

Baseline: 6 (4-9)

Endpoint: 7 (3-9)

Levetiracetam and placebo had no effect on median pain intensity (p=0.46).

Comedication

There was no difference in pain

reduction during levetiracetam treatment between patients

treated with concomitant pain medication (n=14) and

patients without concomitant pain medication (n=10)

(P=0.55) or between patients treated with gabapentin and/or pregabalin (n=9) and patients

without gabapentin/pregabalin treatment (n=15) (P=0.95).

Adverse events

14/34=41% patients during levetiracetam had adverse events versus 11/32=34% during placebo.

7 patients were withdrawn because of side effects during levetiracetam treatment and 2 during placebo treatment. The adverse events causing

patients to withdraw from the study during levetiracetam

treatment were incoordination (4), dizziness (3), somnolence

(3), constipation/nausea (3), confusion (1) and rash (1).

There were no statistically significant differences between the two treatment periods.

Small sample size (N=24 analysed)

Concomitant pain medication allowed during the study.

Clinically relevant difference in pain score not defined.

LAMOTRIGINE VS PLACEBO

Finnerup, 2002

Type of study:

Randomized crossover study

Country:

Denmark

Source of funding:

The study was supported by grants from Ludvig and Sara

Elsass’ Founda-tion, the Insti-tute of Experi-mental Clinical

Research Aarhus Univer-sity, the Danish Medical Research

Council, the Danish Society of Polio and Accident Victims, the Foundation for

Research in Neurology, Consul Johan-nes Fogh-Nielsens

and Mrs Ella Fogh-Nielsens legacy, and Jacob Madsen

and Mrs Olga Madsens legacy. Glaxo Wellcome A/S

Denmark provided lamotrigine and placebo tablets

(LAM30044). Pharma 1 Medico Interna-tional Aps

provided hCG test

Inclusion criteria:

Patients with neuropathic pain after traumatic SCI at or below level of spinal lesion; age 18–70 and

pain intensity ≥3 on a 0–10 point numeric rating scale

Exclusion criteria:

known concomitant cerebral damage or dementia (total score on the mini-mental status examination a.m. Folstein

(MMSE) below 26), pregnant or lactating women and fertile

women with inappropriate contraception (a negative pregnancy test was required), previous serious allergic reaction or hypersensitivity to lamotrigine, serious hepatic or renal disease or other significant illness.

N total at baseline:

30

Important prognostic factors²:

Not reported if there were differences in baseline characteristics

Intervention:

Lamotrigine (N=30)

Treatment regimen:

A 1-week baseline period was followed by two 9-weeks

treatment periods with lamotrigine or identical placebo tablets, separated by a 2-week washout period. Tablets containing 25 or 100 mg were administered as single or divided doses. The dose was gradually increased to 400 mg/day: weeks 1,2: 25 mg/day; weeks 3,4: 50 mg/day; week 5: 100 mg/day; week 6: 200 mg/day; week 7: 300 mg/day; and weeks 8,9: 400 mg/day. Patients were permitted to reduce the dose to the previous dosage level if they experienced unacceptable adverse events, but the final dose had to be at least 200 mg and continued for at

least 2 weeks to complete the trial.

Concomitant treatment with spasmolytics (baclofen and

tizanidine), sedatives (zolpidem or zopiclon) for insomnia, and simple analgesics (NSAID or ASA) for other type of pain, was allowed in a constant and unchanged dose during the trial. Paracetamol up to 3 g daily was used as escape

medication; but other drugs with potential pain reducing effect were discontinued 1 week pre-study. On the days of examinations, patients were asked not to take any of the

above mentioned drugs, except for spasmolytics, which were allowed provided they took the same dose on all 3 examination days.

Control intervention:

Placebo (N=30)

Treatment regimen:

See under Intervention

Length of follow-up:

12 weeks

Loss-to-follow-up:

Lamotrigine: 3/30=10%

1 adverse event, 1 new trauma, 1 left country

Placebo: 5/30=17%

2 adverse events, 1 withdrew consent, 1 protocol violation, 1 escape medication

No intention-to-treat analysis; N=22 patients included in analysis

Outcome measures and effect sizes

Primary outcome measure

Change in median weekly pain score from baseline week to the last week of treatment; patients rated daily average overall pain on a numeric rating scale from 0 (no pain) to 10 (worst imaginable pain) using a pain diary.

Change in pain score (from baseline to last week of treatment)

There was no significant effect on pain intensity in the total sample of SCI patients (P=0.11).

The median change in pain score during placebo was 0 and during lamotrigine treatment 1 for the total sample of patients.

Lamotrigine significantly reduced pain compared to placebo in patients with incomplete SCI lesions

(P=0.02, (n=12), while it had no effect on patients with complete injury (n=10).

Adverse events

Adverse events (e.g. CNS, skin, gastrointestinal) and number of patients reporting adverse

events were equally common during lamotrigine and

placebo treatment (n=13 vs n=14 AE and n=5 vs n=4 moderate to serious AE). Only one patient was withdrawn because of a rash and this occurred during the placebo period.

Small sample size (N=22 analysed)

Concomitant pain medication allowed during the study.

AMITRIPTYLINE VERSUS GABAPENTIN VERSUS DIPHENHYDRAMINE

Rintala, 2007

Type of study:

Randomized triple crossover study

Country:

USA

Source of funding:

No commercial party having a direct financial interest in the results of the research

supporting this article has or will confer a benefit upon the author(s) or upon any

organization with which the author(s) is/are associated.

Inclusion criteria:

(1) 18 to 70 years of age, (2) with an SCI at any level and any degree of completeness, (3)

the SCI occurred at least 12 months before entering the study, (4) at least 1 chronic (>6mo) pain component characteristic of neuropathic pain, (5) at least 1 neuropathic pain component rated as at least 5 on a 0 to 10 scale when initially contacted

about participating, and (6) lived within 160km of the medical centre.

Exclusion criteria:

(1) evidence of significant cardiac conduction disturbance, (2) history of seizures, (3) evidence of

liver dysfunction indicative of an infectious process or hepatocellular injury, (4) evidence of renal insufficiency, (5) taking

any contraindicated medications such as maximum acid output

(MAO) inhibitors, (6) current or recent substance abuse problem,

(7) evidence of a previous allergic reaction to any of the study medications, (8) evidence of a serious psychologic disorder

that would prevent giving informed consent or hinder one’s ability to follow through with the study based on the

attending physician’s clinical judgment, (9) evidence of psychologic

or psychosomatic chronic pain based on clinical judgment (no one was excluded based on this criterion), and (10)

pregnancy.

N total at baseline:

38

Important prognostic factors²:

Depression:

CESD-SF score ≥10:12/38=32%

CESD-SF score < 10:24/38=63%

Baseline CESD-SF scores were not available for 2 noncompleters

Intervention A:

Amitriptyline (N=38)

Intervention B:

Gabapentin (N=38)

Treatment regimen:

Each study drug was

administered for 9 weeks. During each of the 3 medication

phases, the daily dose of medication was gradually increased in the first 4 weeks. Daily dosage was kept constant to the extent

possible for weeks 5 through 8; however, if side effects became

too severe, dosages or the number of doses a day were decreased.

The medication was gradually decreased and then discontinued during the ninth week. The tenth week of each medication phase was a washout week similar to the baseline week. Participants were instructed not to take any pain medications other than those we provided at any time during the

study.

Participants were provided tablets containing a combination of 5mg of oxycodone and 325mg of acetaminophen for breakthrough

pain in packets of 8 tablets, 1 packet for each day of the study, from the beginning of the baseline week through the washout week after the third medication (maximum, 217d; 1736 tablets). Participants were instructed to take the tablets only if necessary and to start a new packet each day.

The maximum doses in this study were 50mg, 3 times daily

for amitriptyline and 1200mg, 3 times daily for gabapentin.

Control intervention:

Diphenhydramine (N=38)

Treatment regimen:

Maximum individual dose was 25mg, 3 times daily, and that dose was kept constant for the entire 9-week phase.

Participants received 1 dose a day for the first 3 days, 2 doses a day for the next 2 days, and 3 a day thereafter through week 8. During week 9 they received 2 doses a day for 2 days and 1

dose a day for 2 days, to gradually discontinue the medication.

We used diphenhydramine as the control medication because it is not a pain reliever but does have some side effects, such as drowsiness and dry mouth, which are similar to side effects of

the other 2 medications. This fact helped maintain the double

blind design.

Length of follow-up:

30 weeks

Loss-to-follow-up:

16/38=42% dropped out due to adverse effects, medical problems, protocol violation, moving out of state.

A dropout was defined as a participant who was unable to complete at least the first 8 weeks of a given medication phase.

There was no

significant difference between the completers and the noncompleters

on baseline variables (e.g. pain intensity, duration of pain, baseline CESD-SF, level and completeness of SCI).

No ITT analysis.

Outcome measures and effect sizes

Primary outcome measure

Final pain rating (pain on average for week 8 for each medication) as measured

by the VAS.

The proportion of participants whose pain intensity decreased at least 30% was calculated for each medication within the 2 depressive symptomatology

Groups (CESD-SF scores < 10 or ≥ 10). A change of 30% or better is considered to be a minimal clinically important difference.

Average VAS pain score (during week 8)

Mean (SD)

Amitriptyline (N=22):

3.46 (2.09)

Gabapentin (N=22):

4.85 (2.86)

Diphenhydramine (N=22):

5.11 (2.54)

The average pain intensity in week 8 with amitriptyline therapy was significantly

lower than with gabapentin therapy (p=0.03), or diphenhydramine therapy (p=0.012). There was no significant difference between

gabapentin and diphenhydramine therapy.

High vs. low CESD-SF scores:

Baseline VAS scores for participants with low

(<10) CESD-SF scores (n=14) was 4.61 and for those with high

scores (≥10) (n=8) it was 7.41. At week 8, in participants with high

baseline CESD-SF scores, amitriptyline (mean, 4.21) was more effective than diphenhydramine (mean, 6.67; P=0.035), and there was a nonsignificant trend suggesting that amitriptyline may be more effective than gabapentin (mean, 6.68; P=0.061).

Gabapentin was no more effective than diphenhydramine

(P=0.97). There was no significant difference among the medications for those with lower CESD-SF scores.

% participants whose pain intensity decreased at least 30%

Among the participants in the low CESD-SF group, the percentages with at least a 30% decrease from baseline in pain intensity were 50% with amitriptyline, 42.9% with gabapentin, and 35.7% diphenhydramine. Among participants in the high

CESD-SF group, the percentages were 62.5, 12.5, and 25, respectively.

Not reported if the differences were statistically significant.

Adverse events

Dry mouth was by far the most frequent complaint, with 21 of

22 completers reporting having had it at least once. Among the

completers during amitriptyline therapy, 5 side effects— dry

mouth, constipation, difficulty emptying the bowel, nausea, and difficulty emptying the bladder—were significantly more frequently reported than during therapy with the other 2 medications.

Withdrawal or early cross-over because of possible side effects occurred 4 times during the amitriptyline phase: (1) light-headedness, drowsiness, pain in the lower abdomen, flushing, rapid heart beat, and chills ; (2)

allodynia and pins and needles feeling in extremities ; (3) suicide ideation; and (4) drowsiness, dizziness, and falling out of a wheelchair.

And 5 times during the gabapentin phase: (1) shortness of breath 1); (2) dizziness, fatigue, and nausea ; (3) increased spasticity and pain; (4) fatigue, drowsiness, constipation, and dry mouth and (5) severe itching. Possible side effects caused an early crossover twice during the diphenhydramine phase: (1) palpitations and (2) fatigue, dizziness, and drowsiness .

High drop-out rate (42%).

Concomitant pain medication not allowed during the study. Breakthrough medication was allowed. Statistical analysis revealed no differences in use between the groups (amitriptyline: 1.88 tablet/day, gabapentin: 2.1 tablet/day, diphenhydramine: 2.02 tablet/day).

The small number of completers precluded

from conducting the planned ANOVA while controlling for

numerous factors such as sequence of medications, dose of medication, and amount of medication taken for breakthrough

pain. These factors had to be examined individually and did not appear to influence the main outcome measures

of pain intensity.

All measures were

based on self-reports.

It is also important to remember that amitriptyline has considerable side effects, some of which can be serious, particularly in the SCI population—as reflected by this study’s exclusion criteria. Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction,

and a lowering of the seizure threshold.

DULOXETINE VS PLACEBO

Vranken, 2011

Type of study:

RCT

Country:

Netherlands

Source of funding:

Not reported.

There are no conflicts of interest.

Inclusion criteria:

age 18 years or older; written informed consent; suffering from severe neuropathic pain, visual analog scale score six and higher caused by lesion or dysfunction in the central nervous system. The pain had to persist for at least six months, and had started after sustaining the lesion or dysfunction in the central nervous system. Additionally, the disease process or lesion affecting the central somatosensory system had to be concordant with the distribution of pain. Patients taking concomitant analgesic medication were allowed to enter the study if neuropathic pain treatment was on a stable regimen at least six weeks before start of the study. Analgesic treatment

with antidepressants, however, was to be discontinued at least

30 days before receiving study medication. No new analgesic therapies were to be initiated at any time during the trial.

Exclusion criteria:

Patients who were pregnant; had a history

of intolerance, hyper-sensitivity, or known allergy to duloxetine;

had a known history of significant hepatic, renal, or psychiatric disorder; using antidepressants for treatment of depression

N total at baseline:

48

Important prognostic factors²:

The two groups (n = 24 per group) were similar with respect to baseline demographic and disease

characteristics (diagnosis, baseline pain intensity, quantitative sensory testing, and analgesic treatment)

Intervention:

Duloxetine (N=24)

Treatment regimen:

treatment with a flexible-dose placebo (1 to 2 capsules a day) or flexible-dose duloxetine (1 to 2 capsules of 60 mg/day). Patients received escalating doses of either duloxetine (60 and 120 mg/day,) or matching placebo capsules (daily orally intake of 1 or 2 capsules) titrated at a one-week interval based on response and tolerability. In both groups, patients started with one capsule per day (contain-

ing either 60 mg of duloxetine or placebo). If the response (i.e. pain

relief) was insufficient (defined as a pain reduction of less than 1.8

on a visual analog scale), patients were given two capsules (i.e. two

capsules of either 60 mg of duloxetine or placebo). All patients received, respectively, active medication or matching placebo capsules and followed the same oral dosing schedule (once daily in

the evening). A single downward dose titration after a one-week-

interval was allowed, after which the patient remained on the final

dosage during the remainder of the study period.

Control intervention:

Placebo (N=24)

Treatment regimen:

See under Intervention

Length of follow-up:

8 weeks

Loss-to-follow-up:

Two patients withdrew after randomization, before taking any study medication and were not included in the ITT population. They were replaced by the first consecutively screened patients with identical prognostic charac-

teristics to prevent disturbing the randomization procedure by

the method of minimization.

Data were analyzed on an intention-to-treat basis (ITT) including the patients who received at least one dose of randomized study medication

Outcome measures and effect sizes

Primary outcome measure

Pain intensity score recorded by the patients (at baseline,

end of each week, and eight weeks following treatment), on a visual analog scale (VAS), using a pain diary. The mean pain score (in both groups) at the end was based on the average of nine (VAS) pain scores measured regularly during the last 72 h of treatment.

Change in VAS pain score (before and after 8 weeks treatment)

Mean (SD)

Duloxetine (N=24):

Baseline: 7.1 (0.8)

Endpoint: 5.0 (2.0)

Change: 2.1

Placebo (N=24):

Baseline: 7.2 (1.26)

Endpoint: 6.1 (1.7)

Change: 1.1

A trend towards a statistically significant decrease in mean pain score at endpoint was observed for duloxetine

treatment compared with placebo treatment (p = 0.056).

No difference in response to duloxetine was observed between patients with spinal

cord injury (n = 18) and patients with stroke (n = 6) (p = 0.61).

Adverse events

The most frequently reported adverse events were central

nervous system-related (dizziness, decreased intellectual performance, and somnolence) and nausea. The incidence of these adverse events (mild or moderate in intensity) did not differ significantly between treatment groups. Somnolence, however, was reported significantly more frequently in the duloxetine-treated patients (p = 0.003).

Mixed study population:

Duloxetine:

N=18 SCI and N=6 stroke

Placebo:

N=16 SCI N=8 stroke

Concomitant pain medication allowed during the study.

TRAMADOL VS PLACEBO

Norrbrink, 2009

Type of study:

RCT

Country:

Sweden

Source of funding:

This study was made possible by grants from the Norrbacka-Eugenia

Foundation

Inclusion criteria:

signed informed consent, SCI > 12 months, pain classified as neuropathic pain at or below the level of lesion14 and of a duration of more than 6 months, fluency in Swedish, and no known

cognitive impairment. Pain intensity ratings of either the general or the worst pain intensity in the last week were required to be equivalent to or more than 3 on Borg’s

Category Ratio (CR-10) scale, a combined numerical and verbal rating scale. The patients had to be naive to

treatment with tramadol and have had no signs of

intolerance to treatment with opioids in the past. If patients were currently using opioids or anti-depressants, inclusion

was decided on an individual basis.

Exclusion criteria:

Patients who were pregnant or lactating

N total at baseline:

36

Important prognostic factors²:

Patients randomized to the active drug and placebo groups differed regarding level of injury with more patients

with paraplegia being randomized to treatment with placebo. Patients in the placebo group also reported higher levels of pain and some associated variables at baseline. Twenty of the 35 (57%) patients were on

concomitant analgesic medication (including antiepileptic drugs or antidepressants); 14 (61%) in the tramadol group

and 6 (50%) in the placebo group.

Intervention:

Tramadol (N=23)

Treatment regimen:

Four week treatment. The initial dose was 50-mg tramadol (1 tablet) or 1 placebo tablet 3 times daily according to recommendations in The Swedish Drug Compendium published by the Swedish Association of the Pharmaceutical Industry. Patients were thereafter

instructed to increase the dose every 5 days by 50mg (1 placebo tablet) until a maximum dose of 400mg daily (8 placebo tablets) was reached. If optimal pain relief was

obtained or if adverse events became intolerable before

maximum dose was reached, patients were instructed to stop increasing their dose. Patients experiencing intolerable adverse events were withdrawn from the study and if they were receiving the active drug, they were asked to phase out the drug by 50mg/d.

During the study, patients were allowed to continue stable pain medication and asked not to make any changes in their current dosages.

Control intervention:

Placebo (N=12)

Treatment regimen:

See under Intervention

Length of follow-up:

4 weeks

Loss-to-follow-up:

Tramadol: 11/23=48%

Placebo: 2/12=17%

One withdrawal was for drug-unrelated

factors (rib fracture), but the remaining patients stopped medication because of adverse events.

Unknown: N=1 never began drug treatment after enrolment.

ITT analysis (data analyses were performed on

the intention-to-treat population defined as all patients who

were randomized and had taken at least 1 dose of study

medication. Data from those patients who dropped out or

were withdrawn prematurely were replaced using the last-observation-carried-forward approach)

Outcome measures and effect sizes

Primary outcome measure

Pain intensity

Measured on Borg’s

Category Ratio (CR -10) scale, a combined numerical and

verbal rating scale.

Change in pain intensity (CR-10)

Median (IQR):

Present pain intensity

Tramadol

Baseline: 3 (2.5;5)

Week 4: 3 (2;4)

Placebo

Baseline: 5 (4.5;5.5)

Week 4: 5.5 (3.5;7)

General pain intensity

Tramadol

Baseline: 4 (3;5)

Week 4: 3 (2.5;5)

Placebo

Baseline: 7 (4.5;7)

Week 4: 6.5 (5;7.25)

Worst pain intensity

Tramadol

Baseline: 7 (5;8)

Week 4: 5 (4;7)

Placebo

Baseline: 9 (7;10)

Week 4: 8 (7;10)

Between-group differences (tramadol vs. placebo) in

ratings of present pain, general pain, and worst pain

intensity were significant (P<0.05).

Adverse events

Twenty-one (91%) patients experienced 1 or more

adverse events on active medication and 7 (58%) on

placebo (P=0.02). More moderate to severe adverse

events were reported for the active drug than for the

placebo. The most commonly reported adverse

events of tramadol were tiredness (74%), dry mouth (52%), and dizziness (52%). Constipation was the most commonly reported side-effect of the placebo (33%).

Small sample size (not reported how many patients were included in ITT analysis)

High loss to follow-up in tramadol group (48%) due to adverse effects.

Clinically relevant difference in pain score not defined.

Baseline differences between groups (level of injury, pain levels, concomitant analgesics)

Concomitant pain medication allowed during the study.

LIDOCAINE VS PLACEBO

Finnerup, 2005

Type of study:

Randomized crossover study

Country:

Denmark

Source of funding:

Supported by grants from the

Ludvig og Sara Elsass’ Foun-dation; the Agnes and Poul

Friis Founda-tion; the Institute of Experimental Clinical

Research, Aarhus University; the Sahva Founda-tion; the Danish Medical Research Council and The Danish Society of Polio and Accident Victims

Inclusion criteria:

Patients aged 18 yr or older with neuropathic pain at or below the level of injury due to trauma or disease of the spinal cord or cauda equina with a median pain intensity

of 3 or more on a 0- to 10-point numeric rating scale

during a 1-week baseline period

Exclusion criteria:

Known concomitant cere-

bral damage or dementia (total score on the Mini-Mental State Examination a.m. Folstein below 26), pregnancy or lactation, alcohol or substance abuse, mental disease,

hypersensitivity to lidocaine, cardiac or circulatory disease, or severe nephropathy (glomerular filtration rate

below 35 ml/min)

N total at baseline:

26

Important prognostic factors²:

N=13 with and N=13 without evoked pain

N=15 traumatic cause SCI and N=9 non-traumatic cause of SCI (N=2 not reported)

Intervention:

Lidocaine (N=26)

Treatment regimen:

A 1-week baseline period was followed by two treatment sessions separated by at least 6 days and followed by a 1-week period. Identical 250-ml infusions of lido-

caine (5 mg/kg) or saline (0.9% NaCl) were administered intra-venously over a 30-min period.

Concomitant treatment with spasmolytics (baclofen and tizanidine), gabapentin, opioids, and simple analgesics (nonsteroidal antiinflammatory drugs, parace-tamol, or acetylsalicylic acid) for pain was allowed in a constant and unchanged dose during the trial. On the day of examinations, patients were asked not to take

any of the above-mentioned drugs, although they were allowed provided they took the same dose on the two treatment sessions.

Control intervention:

Placebo (N=26)

Treatment regimen:

See under Intervention

Length of follow-up:

Unclear

Loss-to-follow-up:

2/26= patients withdrawn before any treatment was given; one dropped out for personal

reasons, and one was excluded because of a low pulse before the first treatment.

No intention-to-treat analysis; N=24 patients included in analysis

Outcome measures and effect sizes

Primary outcome measures

- Change in pain score from baseline to the end of the infusion using the lowest of the two scores (at 25 and 35 min); patients scored their current spontaneous pain on a visual analog scale of 0–100 

- Difference in number of responders (patients with at least 33% pain reduction) between the two groups

Change in VAS pain score (from baseline to the end of the infusion)

Lidocaine significantly reduced pain compared with placebo in the total sample of SCI patients (independent of the presence or absence of evoked pain) (P<0.01) (mean change not reported)

Difference in number of responders (≥33% pain reduction)

Significantly more patients were

responders to lidocaine (n=11) than to placebo (n=2) (P=0.008)

Adverse events

e.g. somnolence, dizziness, dysarthria, lightheadedness, blurred vision, tremor

lidocaine: 19/26=73%

placebo: 1/26=3.8%

Small sample size (N=24 analysed)

High proportion of patients (73%) with adverse events due to lidocaine.

Concomitant pain medication allowed during the study.

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate  concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

GABAPENTIN VERSUS PLACEBO

Levendoglu, 2004

Unclear.

It is not reported how allocation sequence was generated.

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Both GBP and placebo were provided as identically appearing capsules.

Unlikely.

Before increasing the dosage at each interval, the subject was seen by a blinded physician to document any adverse effects.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unlikely.

No patients lost to follow up.

Unlikely.

No loss to follow up.

Tai, 2002

Clear.

Pharmacist used random distribution table.

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Both GBP and placebo were provided as identically appearing capsules and each group received same number of tablets.

Unlikely.

Before increasing the dosage at each interval, the subject was seen by an SCI physician, who was unaware of treatment allocation, to document any adverse effects.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Likely.

7/14 (50%) lost to follow-up (N=1 side effect, N=2 medical complications not related to study, N=4 lack of compliance).

Likely.

No ITT analysis

PREGABALIN VERSUS PLACEBO

Siddall, 2006

Clear.

Randomization schedule which was computer generated and used a block size of four.

Unclear.

Not reported if patients and investigators could not foresee assignment

Unlikely.

Medication was

blinded by using capsules of identical size, color, taste, and smell for placebo and pregabalin.

Unclear.

Due to high dropout rate in placebo group (lack of efficacy) care providers may have  had assumptions concerning treatment assignment

Uclear.

Due to high dropout rates in both groups  (lack of efficacy, adverse events) patients may have  had assumptions concerning treatment assignment

Unlikely.

Measures as described in the methods are reported in the results.

Likely.

High percentage of withdrawals.

Pregabalin:

21/70=30%

Withdrawn because of: adverse events (15), lack of efficacy (5), other (1)

Placebo:

30/67=45%

Withdrawn because of: adverse events (9), lack of efficacy (20), other (1)

Likely.

ITT analysis based on the last observation carried forward (LOCF). This method assumes that the participant's responses (e.g., outcome measures) would have been stable from the point of dropout to trial completion, rather than declining or improving further. It also assumes that missing values are “missing completely at random” (i.e., that the probability of dropout is not related to variables such as disease severity, symptoms, group assignment or drug side effects). Due to high dropout rate (in placebo due to lack of efficacy and in pregabalin group due to AE), this method may overestimate

actual treatment effects.

Cardenas, 2013

Clear.

Investigators used the sponsor’s interactive response technology system (via phone or internet) to screen, randomize, and assign treatment to patients in a double-blinded manner. The system provided a unique identification number for each patient at screening.

Unclear.

Not reported if patients and investigators could not foresee assignment

Unlikely.

Both placebo and pregabalin were identical in the form of

gray capsules.

Unclear.

Not reported how care providers were blinded (flexible dose adjustment based on tolerability).

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unlikely.

Pregabalin:

19/112=17%

8 adverse event, 5 protocol violation, 3 withdrew, 1 lack of efficacy , 2 other

Placebo:

17/108=16%

1 did not receive intervention, 8 adverse event, 3 protocol violation, 3 withdrew, 2 lack of efficacy

Unclear.

Modified intention to treat (mITT) analysis which included all patients who took at least 1 dose of study medication and excluded 8 patients who were randomized before the protocol was amended on February 12, 2008.

Not in (mITT) analysis:

Pregabalin: 3/108=3%

Placebo: 6/112=5%

GABAPENTIN VERSUS PREGABALIN

Kaydok, 2014

Unclear.

It is not reported how allocation sequence was generated.

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unclear.

The daily oral dose gabapentin was given in three divided doses and daily oral dose pregabalin was given in two dived doses.

Unclear.

The daily oral dose gabapentin was given in three divided doses and daily oral dose pregabalin was given in two dived doses.

Unclear.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unclear.

Gabapentin 3/24=12.5%

Pregabalin: 6/25=24%

Higher proportion discontinued in pregabalin group (due to side effects)

Unclear.

No ITT analysis

Yilmaz, 2015

Unclear.

It is not reported how allocation sequence was generated.

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unclear.

The daily oral dose gabapentin was given in three divided doses and daily oral dose pregabalin was given in two dived doses.

Unclear.

The daily oral dose gabapentin was given in three divided doses and daily oral dose pregabalin was given in two dived doses.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unclear.

Gabapentin: 4/30=13%

Pregabalin: 5/30=17%

Unclear/not reported if difference is significant

Unclear.

No ITT analysis

LEVETIRACETAM VERSUS PLACEBO

Finnerup, 2009

Clear

Assignment to treatment sequence was randomized by a

computer-generated randomization list with a block size of 4

and a consecutive allocation of patients as they entered the

study in each of the three centers

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Use of identical placebo

Unclear.

Not reported if care providers were blinded.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unlikely.

Levetiracetam: 9/36=25%

Placebo: 3/36=8.3%

The withdrawn patients and the study population

did not differ in baseline characteristics

Unclear.

No ITT analysis.

LAMOTRIGINE VERSUS PLACEBO

Finnerup, 2002

Clear.

Assignment to treatment sequence was random via a

computer generated randomization list with blocks of 4,

and patients were allocated consecutively

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Use of identical placebo

Unclear.

Not reported if care providers were blinded.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unclear.

Lamotrigine: 3/30=10%

Placebo: 5/30=17%

Unclear/not reported if difference is significant

Unclear.

No ITT analysis

AMITRIPTYLINE VERSUS GABAPENTIN VERSUS DIPHENHYDRAMINE

Rintala, 2007

Clear.

Eligible participants were randomized into 1 of 6 groups. The order of this assignment within the sets of 6 was based on a table of random  numbers, and varied from set to set.

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

All 3 medications were prepared by a commercial com-

pounding pharmacy and placed in identical capsules according

to the dosing schedule. Inactive filler, sodium bicarbonate, was

used for 1 or 2 doses a day while gradually increasing or

decreasing the total daily dose. In our

study, amitriptyline was provided in 3 daily doses rather than 1

dose at bedtime because gabapentin was taken 3 times daily

and we wanted to keep the treatments as similar as possible

Unlikely.

See under blinding of participants.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unclear.

16/38 (42%) dropped out  mainly due to adverse effects/ medical problems.

There was no significant difference in dropout rate among the medications.

There was a difference in number of oxycodone -acetaminophen tablets taken during baseline week: mean 16.9 (median 12.5) in completers group versus mean 22.3 (median 22) in non-completers group).

Unclear.

No ITT analysis

DULOXETINE VERSUS PLACEBO

Vranken, 2011

Clear.

Computer-generated randomization list

Unlikely.

The association between type of treatment and study code was only known at CEBB and at the hospital pharmacy department.

Both departments were not involved in patient care.

Unlikely.

identical capsules of duloxetine or placebo. All patients received,

respectively, active medication or matching placebo capsules

and followed the same oral dosing schedule.

Unlikely.

At baseline each coded medication bottle was supplied

by the hospital pharmacist to the blinded treating physician. Patients,

pain specialists, and all other health care personnel involved

in the conduct of the study were blinded to individual treatment

assignments for the duration of the study.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Unlikely.

Two patients withdrew after randomization, before taking any study medication and were not included in the ITT population. They were replaced by the first consecutively screened patients with identical prognostic charac-

teristics to prevent disturbing the randomization procedure by

the method of minimization.

Unlikely.

Data were analyzed on an intention-to-treat basis (ITT) including the patients who received at least one dose of randomized study medication

TRAMADOL VERSUS PLACEBO

Norrbrink, 2009

Unclear.

It is not reported how allocation sequence was generated. Randomization in a 2:1 ratio (tramadol: placebo)

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Patients were blinded. The active and the placebo drugs were

identical in appearance

Unclear.

Not reported if care providers were blinded.

Unlikely.

Patients were outcome assessors (self- reporting of pain scores)

Unlikely.

Measures as described in the methods are reported in the results.

Likely.

Tramadol: 11/23=48%

Placebo: 2/12=17%

High withdrawal rate in tramadol group due to adverse effects.

Unlikely.

35/36 patients were included in ITT analysis based on all patients taking at least 1 dose of study medication)

LIDOCAINE VERSUS PLACEBO

Finnerup, 2005

Clear.

Assignment to treatment sequence was random via a

computer-generated randomization list with a block size of four and consecutive allocation of patients as they en-

tered the study

Unclear.

Not reported if patients and investigators could not foresee assignment.

Unlikely.

Identical 250-ml infusions of lidocaine

(5 mg/kg) or saline (0.9% NaCl) were administered.

Unclear.

Not reported if care providers were blinded.

Unlikely.

The primary outcome measure and pain relief was evaluated by an investigator unaware of symptomatology,

group assignment, and possible adverse effects.

Unlikely. Measures as described in the methods are reported in the results.

Unlikely.

In each group one patient dropped out before any treatment was given.

Unclear.

No ITT analysis