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.