TABLE 1.
Summary of clinical and preclinical primary efficacy assessment endpoints for translation of current licenced medicines for painful diabetic peripheral polyneuropathy.
| Licenced/recommended medicine year of approval in Europe daily dose (mg) | RCT Primary and secondary endpoints | Preclinical neuropathic pain model | Preclinical efficacy MED | Primary stimulus evoked sensory endpoints | Translation |
|---|---|---|---|---|---|
|
a
Pregabalin Lyrica®, (2004) 300–600 mg/day |
↓ Pain intensity/quality (weekly SF-MPQ VAS score) ↓ sleep interference score Freynhagen et al. (2005), Rosenstock et al. (2005), Richter et al. (2005) |
STZ (50 mg kg ip rat) | 3 mg kg po 10 mg kg po |
↓VFH (static allodynia) ↓VFH (Dynamic allodynia) Field et al. (1999) |
a Forward |
| Gabapentin Neurontin®, (2002) 900–3,600 mg/day |
↓ Pain intensity (weekly 11-point Likert score) ↓QoL, ↓sleep interference score Backonja (1998), Morello et al. (1999), Simpson et al. (2001) |
STZ (50 mg kg ip rat) CCI (rat) SNL L5/6 (rat) |
10 mg kg po, 10 μg i.t. 30 mg kg po, 1 μg i.t. 30 mg kg po, 100 mg kg ip 100 mg kg ip |
↓VFH (static allodynia) ↓VFH (Dynamic allodynia) ↓VFH (static allodynia) ↓PWL (cold water allodynia) ↓VFH (static allodynia) Hunter et al. (1997), Field et al. (1999), Field et al., (2002) |
Back/Forward (Bidirectional) |
| Amitripyline 25–100 mg/day (recommended) |
↓Pain intensity (weekly 11-point Likert score, VAS) ↓sleep interference score/daily activities Max et al. (1992), Biesbrock et al. (1995), Morello et al. (1999) |
STZ (50 mg kg ip rat) CCI (rat) SNL L5/6 (rat) |
0.5 mg kg po 1.5 mg kg sc 10 mg kg ip, 60 μg i.t., 100 nmol ipl |
↓VFH (static allodynia) No effect (Dynamic allodynia) ↓tonic pain score ↓PWL (Thermal hyperalgesia) No effect (static allodynia) Ardid and Guilbaud (1992), Field et al. (1999), Esser and Sawynok (1999) |
Back/Forward (Bidirectional) |
| Duloxetine Cymbalta® (2005) 60–120 mg/day |
↓Pain intensity (weekly 11-point Likert score) ↓QoL No change in dynamic allodynia Wernicke et al. (2006), Goldstein et al. (2005), Raskin et al. (2006) |
STZ (50 mg kg ip rat) STZ (200 mg kg ip mouse) SNL L5/6 (rat) |
20 mg kg po 20 μg i.t. 20 mg kg po 20 mg kg po |
↓VFH (static allodynia), ND (Dynamic.allodynia) ↓PWL (Thermal hyperalgesia) ↓VFH (static allodynia) Iyengar et al. (2004), Mixcoatl-Zecuatl and Jolivalt (2011), Kuhad (2009) |
Back/Forward (Bidirectional) |
Recommended first-line treatment, RCT (randomised clinical trial), MED (minimum effective dose), STZ (streptozocin), CCI (chronic constriction injury), SNL (spinal nerve ligation), VFH (Von Frey hair), PWL (paw withdrawal latency), ND (not determined), i.t. (intrathecal), po (oral), ip (intraperitoneal), visual analogue scale (VAS), ipl (intraplantar) of the Short-Form McGill Pain Questionnaire (SF-MPQ), QoL (measures of quality of life (Short Form–36 Quality of Life Questionnaire and Profile of Mood States)), Equivalent therapeutic human doses are not determined in preclinical studies as drug plasma concentrations are not reported.