Table 3

Summary of included trials

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.


Douglas 2008 [41] (A) [linked to Douglas 2006 [31]]

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".


Stacey 2008 [29] [linked to D'Urso De Cruz 2005; D'Urso De Cruz 2005; Siffert 2005 [42-44]]

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".


Robert 2005 [25](A)

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".


Argyra 2005 [35](A)

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


*All trials are single arm, unless otherwise stated. The type of trial was as reported by the authors. (A) indicates that only a conference abstract was available. NR; Not reported. All studies were prospective in design, with the exception of two [21,32]. Studies which do not use the licensed dose of the intervention and/or do not study the use of the intervention in a licensed indication are italicised (UK license, as reported by the European Medicines Agency (EMA) for pregabalin and duloxetine and the MHRA UK license for the lidocaine plaster, which was licensed by country rather than centrally by the EMA). **Fibromyalgia patients were also enrolled in this study, however data for these patients were reported separately and were not extracted for this review. ***Patients with radiculopathy are assumed to have radiculopathy with a neuropathic component as the studies state that patients with neuropathic conditions are included.

Plested et al. BMC Neurology 2010 10:116   doi:10.1186/1471-2377-10-116

Open Data