Jakob Vormstrup Holbech, Anne Jung, Torsten Jonsson, Mette Wanning, Claus Bredahl, Flemming W Bach

Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round's summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors - as well as for other potential combinations. The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.