Background
Methods
Literature searches
Inclusion/Exclusion criteria
Criteria | Included | Excluded |
---|---|---|
Type of study | All study designs, both prospective and retrospective (except case studies for one patient) | Case studies for one patient |
Population | Adult patients NeP due to any cause (central or peripheral) Treatment-refractory NeP (as defined in the included studies) | Studies in children Treatment naive patients |
Study size | Any | None |
Trial length | Any | None |
Interventions | Pregabalin Lidocaine plaster Duloxetine | Other treatment for NeP |
Comparator | Any/None | - |
Language | English language only | Non-English language |
Study procedures
Critical appraisal
Reporting | Did the study address a clearly defined issue? |
Did the authors use an appropriate method to answer the review question? | |
Are the main outcomes, patient population and interventions tested clearly described? | |
Are losses to follow-up reported and clearly described? | |
Bias and confounding effects | Were the patients recruited in an acceptable way? |
Was any attempt to randomise or blind patents or investigators reported? | |
Have the authors identified all/any of the confounding factors? | |
Was the follow-up of patients complete and long enough? | |
Usefulness of the study | Are the results useful to answer the review question? |
Do the results fit with the evidence from other studies? |
Analysis
Results
Trial Flow
Trial Characteristics
Study reference | Study location | Type of trial* | Study duration | No. pts | Treatment and dose | Study population | % pts refractory | Reporting and definition of refractory |
---|---|---|---|---|---|---|---|---|
Pregabalin | ||||||||
Freynhagen 2007 [27] |
Germany
|
Single-arm trial
|
4 weeks
|
55
|
Pregabalin titrated from 75-600 mg/day
|
Polyneuropathy, chronic radiculopathy***, encephalitis disseminate, PHN, neuropathic cancer pain, acute herpes zoster infection, CRPS (CRPS II), other
|
100%
|
Diagnosis stated by the referring physician as "refractory NeP", "intractable NeP", "problematic NeP" or similar wording.
Definition not reported. |
Obermann 2008 [33] |
Germany
|
Single-arm trial
|
52 weeks
|
53
|
Pregabalin titrated from 50-75 mg/d
Mean (SD) dose 245 (77) mg/d at day 14
|
TN with and without concomitant facial pain. |
94%
|
All but three of patients had received prior therapy, therefore may be considered refractory. |
Sommer 2007 [34] |
Germany
|
Single-arm trial
|
Unclear (mean duration of continuous pregabalin intake 217 days)
|
19
|
Pregabalin 75 mg bid was titrated.
Mean effective dose (SD); 305 (185) mg
|
Restless Leg Syndrome with; Polyneuropathy, small fibre neuropathy, neurinomata. |
89%
|
All but two patients had received prior therapy, therefore may be considered refractory.
Reasons for discontinuation of therapy were lack or loss of efficacy, side effects and/or augmentation. |
Ambesh 2008 [24] (A) | Unclear | Unclear, active controlled | Follow-up was 2-18 months | 86 | Gabapentin 300 mg tid Gabapentin 150 mg and Pregabalin 75 mg bid Pregabalin 150 mg bid | NeP. | 100% | Patients are "resistant to current analgesic treatment regimens or conventional pain therapies". Patients with "intractable NeP". Definition not reported. |
Allen 2005 [26] (A) | UK | Single-arm trial | Up to 6 months | 18 | Mean dose of pregabalin was 600 mg/day | NeP. | 100% | Patients with NeP "inadequately controlled by gabapentin". Definition of refractory not reported. |
UK | Audit | Data reported for 3 months | 30 | Pregabalin dosing "according to BNF recommended standard regime" | NeP. | 100% | Patients who "failed to respond to or who had been unable to tolerate first and second-line neuropathic pain agents". | |
Hanu-Cernat 2005 [32] (A) | UK | Audit | Not stated | 47 | Dosing not stated | Variety of NeP conditions. | 100% | Patients with an "unsatisfactory response to drugs". Patients who were previously treated with gabapentin which "failed to relieve the symptoms" or where the "dose could not be escalated due to side-effects". |
United States | Single-arm trial | 65 weeks | 81 | Pregabalin 150 mg/day titrated up to a max of 600 mg/d | DPN, PHN** | 100% | Patients refractory to at least 6 months of usual care for NeP. Definition of refractory; discontinuation of a medication due to the inadequate effectiveness after 2 weeks of treatment at the minimum recommended doses, intolerable adverse events, or both. | |
Toth 2007 [30] (A) | Unclear | Single-arm trial | Unclear (Av. treatment duration 26 weeks) | 33 | Average dose 375 mg of pregabalin | NeP due to PN. | 30% (only data on refractory patients-i.e. non-responders to gabapentin was extracted) | Responders and non-responders to gabapentin. Definition of non-responders not reported. |
Lidocaine plaster
| ||||||||
Galer 1999 [22] |
United States
|
RCT, placebo controlled
Enriched enrolment design
|
4 weeks (28 days max.)
|
32
|
Lidocaine 5% plaster (700 mg/plaster) applied as 3 plasters per day to the PHN region
Placebo plaster, 3-5 plasters/day (10 × 14 cm)
|
PHN
|
Unclear
|
Compassionate use protocol enrolling patients who were participants of a previous study of the lidocaine plaster who had requested open-label use and those who were "refractory PHN patients".
Definition of refractory not reported. |
Hines 2002 [21] |
United States
|
Case series
|
Not stated
|
4
|
Lidocaine plaster 5% (Lidoderm)
|
Low back pain (2 patients with neuropathic component, 1 patient unclear if neuropathic component; lumbar degenerative disc disease, L4-L5 arthrodesis, and complex regional pain syndrome type 2 in 1 patient)
|
100%
|
All patients had previous treatment. The definition of refractory varied across patients from inadequate control of symptoms to intolerant of treatment. |
Devers 2000 [28] |
United States
|
Single-arm trial
|
Mean duration 6.2 weeks
|
16
|
Up to 3 plasters directly to the painful area
Wear plasters up to a max 12 hours/day
|
NeP due to: Postthoractomy, Stump neuroma, Intercostal neuralgia, Abdominal neuroma
Radiculopathy***, Meralgia paresthetica, CRPS type 1, Diabetic polyneuropathy, Postmastectomy
|
100%
|
All patients had been enrolled in prior drug trials, of which were unsuccessful; "either resulted in intolerable side effects of inadequate partial pain relief". |
Unclear
|
Case series
|
Not stated
|
3
|
Lidocaine plaster 5%
|
Central NeP syndromes due to: Spinal injury, IV infusion of infliximab
|
100%
|
All patient had been treated with previous therapy, however all "patients continued to experience excruciating pain". | |
Unclear
|
Single-arm trial
|
Unclear (length of treatment 2 months-4 years, mean 18 months)
|
36
|
Lidocaine 5% plaster
Two plasters used every 24 hours
|
PHN, Posthoracotomy syndrome, Post mastectomy pain, DPN, CRPS, Peripheral ischaemia due to autoimmune disease
|
100%
|
Patients "resistant to therapy". | |
Galer 2004 [20] |
United States
|
Single-arm trial
|
6 weeks
|
71
|
Lidocaine plaster 5% daily, max. 4 plasters
|
Low-back pain (enrolled patients with non-radicular LBP, who reported moderate-to-severe pain on the neuropathic pain scale at study enrolment)
|
100%
|
Patients with the "moderate to severe pain ... at baseline despite prn or stable doses" of previous treatment. |
Galer 2003 [36] |
Unclear
|
Survey
|
Not reported (mean length of plaster use 7.6 years)
|
20
|
Lidocaine 5% plaster; the mean number of plasters applied to the PHN region was 2.3/d (range 1-5/day)
|
PHN
|
100%
|
The conclusion states that this study assessed "long term pharmacotherapeutic for a refractory neuropathic pain condition". Subjects were offered "compassionate use of the lidocaine plaster". |
Duloxetine | ||||||||
Restivo 2008 [23] |
Greece
|
Unclear, active controlled
|
12 weeks
|
18
|
Duloxetine 60 mg/day
Duloxetine 120 mg/day
|
TN
|
100%
|
Patient were "refractory to medical treatment".
Definition not reported
|
Treatment | Licensed indication | Types of NeP studied within license | Types of NeP studied outside of license |
---|---|---|---|
Pregabalin | Peripheral and central NeP | • NeP (variety) | |
• Polyneuropathy | |||
• Chronic radiculopathy with a neuropathic component | |||
• PHN | |||
• Diabetic peripheral NeP | |||
• Neuropathic cancer pain | |||
• CRPS (CRPS II) | |||
• TN | |||
• Restless Leg Syndrome with NeP | |||
Lidocaine plaster | PHN | • PHN | • Lower back pain with a neuropathic component |
• CRPS | |||
• NeP due to | |||
• Postthoractomy | |||
• Stump neuroma | |||
• Intercostal neuralgia | |||
• Abdominal neuroma | |||
• Radiculopathy | |||
• Meralgia paresthetica | |||
• Diabetic polyneuropathy | |||
• Postmastectomy | |||
• Peripheral ischemia | |||
Duloxetine | DPN | - | • TN |
Study reference | Previous medication | Concomitant/add-on medication |
---|---|---|
Pregabalin | ||
Freynhagen 2007 [27] |
Anticonvulsants (except pregabalin), Antidepressants
Cannabinoids, Gabapentin, Muscle relaxants, NSAID/COX-2 inhibitor, Opioids
|
Analgesics, Non-pharmacological treatment
|
Obermann 2008 [33] |
Carbamazepine, Gabapentin, Oxcarbazepine
|
Carbamazepine, Lamotrigine
|
Sommer 2007 [34] |
Cabergoline, Gabapentin, L-DOPA, Pergolide,
Pramipexole, Roprinole, Roprinole + tilidine, Tilidine
|
Pramipexole + tilidine/naloxone
Pramipexole + fentanyl patch
|
Ambesh 2008 [24] (A) | Current analgesic treatment regimens, Conventional pain therapies | Amitriptyline |
Allen 2005 [26] (A) | Gabapentin | NR |
Tricyclics, Gabapentin | NR | |
Hanu-Cernat 2005 [32] (A) | Gabapentin, Pregabalin | NR |
Anticonvulsants, Gabapentin, NSAIDs/Cox IIs, Opoid analgesics, Pregabalin, SSRI, SNRI, Tramadol, Tricyclics | Tricyclics, Gabapentin | |
Toth 2007 [30] (A) | Gabapentin | NR |
Lidocaine plaster
| ||
Galer 1999 [22] |
Unclear; enriched enrolment design-patients either were treated with the lidocaine plaster and requested open-label use, or were refractory to previous treatment, although type of previous treatment was unclear. |
Acetaminophen, Opiates, NSAIDs, Tricyclics
|
Hines 2002 [21] |
Hydrocodone/acetaminophen, NSAIDs, Sertraline, Diazepam, Rofecoxib, Oxycodone, Progesterone therapy, Gabapentin, Atenolol, Ibuprofen, Opioid analgesics, Clonidine, Citalopram, Olanzapine, Lorazepam, Cyclobenzaprine, Hormone replacement therapy, Hydrocodone, Fluoxetine, Amitriptyline, Venlafaxine, Buspirone
|
Tramadol, Sustained-release diltiazem, Hormone replacement therapy, Triamterene, Amitriptyline, Sertraline, Diazepam, Rofecoxib
Oxycodone controlled-release tablets, Tizanidine, Progesterone therapy, Verapamil, Clonidine, Baclofen
Venlafaxine, Gabapentin
|
Devers 2000 [28] |
Anticonvulsants, Eutectic mixture of local anaesthetics, Lidocaine, Mexiletine, Opoids, Prilocaine (EMLA) cream, Tricyclics
|
Amitriptyline, Acetamenophen, Carbamazepine, Fentanyl patch, Gabapentin, Hydromorphone, Lamotrigine, Methadone, Nortriptyline, Oxycodone, Paroxetine. |
Combinations of conventional anti-neuropathic drugs:
Anticonvulsants, Free radical scavengers, Ketamine, Opioids, Tricyclics. |
NR
| |
NR
|
Lidocaine was tested as an add-on therapy, although other treatments were not reported. | |
Galer 2004 [20] |
Cyclo-oxygenase-2 (COX-2) inhibitors, Non-selective NSAIDs, Gabapentin, Tramadol, Opioids
|
NR
|
Galer 2003 [36] | Topical lidocaine plaster | Anticonvulsants, Acetaminophen, Conticosteroids, Opioids, Tricyclics. |
Duloxetine | ||
Restivo 2008 [23] |
NR
|
NR
|
Trial Quality
Comparison of efficacy outcomes
Intervention | |||
---|---|---|---|
Pregabalin | Lidocaine plaster | Duloxetine | |
Mean Pain Scores-No. studies (no. patients receiving the intervention)
+
reporting reduction in mean pain scores compared to baseline | |||
No. studies reporting data for any pain intensity outcome | 7 | 3 | 1 |
McGill questionnaire | 2* (109) | ||
Pain reduction measured by VRS | 2* (81) | ||
Pain intensity measured by NRS | 1* (30) | 1NR (32) | |
Pain intensity measured by BPI | 2* (73) | ||
Pain score measured by NPS-10, NPS-8 and NPS-4 | 1* (71) | ||
Pain intensity measured by present pain intensity (PPI) | 1* (81) | ||
Percentage pain score reduction | 1NR (16) | ||
Pain severity measured by VAS | 1* (18) | ||
Quality of life-No. studies (no. patients receiving the intervention)
+
reporting improvements in quality of life compared to baseline | |||
No. studies reporting data for any quality of life outcome | 4 | 1 | 0 |
SF-MPQ total, sensory and affective score | 1* | ||
Quality of life measured by the SF-12 | 1* (55) | ||
Sleep interference measured by NRS | 1* (55), 1NS (30) | ||
Quality of sleep measured by VRS | 1* (28) | ||
Quality of sleep (instrument not reported) | 1* (3) | ||
Inference of mood measured by VRS | 1* (28) | ||
Daily activity measured by VRS | 1* (28) | ||
Function interference measured by NRS | 1* (30) | ||
Psychological stress measured by the Short Questionnaire on Current Burden | 1* (55) | ||
Pain associated distress measured by NRS | 1* (30) | ||
PGIC | 1* (18) | ||
Responders-No. studies (no. patients receiving the intervention)
+
reporting data for outcome | |||
No. studies reporting data for any pain relief outcome | 4 | 4 | 0 |
Complete pain relief | 1 (53) | 2 (48) | |
range of percentages reported | 25% | 13-22% | |
A lot of pain relief | 2 (48) | ||
range of percentages reported | 25-34% | ||
Moderate pain relief | 2 (48) | ||
range of percentages reported | 33-44% | ||
Pain reduction of ≥ 50% | 3 (158) | 2 (7) | |
range of percentages reported | 33-49% | 100%
a
| |
Pain reduction 10-50% | 2 (105) | 1 (33) | |
range of percentages reported | 17%
b
| NR
c
| |
Non-responders | 3 (132) | 2 (52) | |
range of percentages reported | 26-46% | 6-20% |
Comparison of quality of life outcomes
Efficacy in patient subgroups
Safety
Study Name | No. of patients | No. with any AE | Comments |
---|---|---|---|
Pregabalin | |||
Obermann 2008 | 53 | 22 | |
Sommer 2007 | 7 | 4 | |
Hanu-Cernat 2005 | 24 | Intolerable side effects occurred in five patients. | |
Lidocaine plaster | |||
Hines 2002 | 4 | 0 | |
Devers 2000 | 16 | 1 | |
Galer 1999 | 32 | No significant difference between lidocaine patch and placebo (p ≥0.492) for AEs that were reported by at least 5% of the subjects in either treatment group. | |
Galer 2003 | 20 | 5 | |
Duloxetine | |||
Restivo 2008 | 18 | 3 | For both treatment groups of duloxetine (60 mg/day and 120 mg/day). |