This chapter assesses the current evidence for synergistic effects of medications in the treatment of neuropathic pain and the options for therapeutic combinations. There are currently a number of animal models, which are widely used to assess the efficacy of neuropathic pain treatments. Such animal models include streptozocin neuropathy as a potential model of peripheral neuropathy and sciatic nerve ligation described in a number of different models as a model of nerve injury. Many studies have consistently shown beneficial effects of combining two agents for the treatment of neuropathic pain, thereby supporting the rationale for combined treatment in humans. Most of the international treatment guidelines for neuropathic pain agree on a set of first-line treatments. These include topical lidocaine for localized peripheral neuropathic pain, antidepressants (Tricyclic antidepressants (TCAs) and Serotonin-norepinephrine reuptake inhibitors (SSNRIs)) and calcium channel alpha-2-delta ligands (gabapentin and pregabalin).