Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study

Abstract

Background Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. Objective This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. Methods This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety. Results One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were − 3.1, − 2.6, and − 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval − 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval − 1.54, − 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. Conclusions All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. Clinical Trial Registratio...

Synergistic interaction between trazodone and gabapentin in rodent models of neuropathic pain

“…Our results, showing that doses of trazodone and gabapentin normally ineffective can be combined to produce therapeutically relevant analgesia, are in line with such hypothesis and, even though they have yet to be confirmed in female animals [ 49 ], they are suggestive of an innovative clinical approach for the treatment of neuropathic pain. The development potential of the combination product is also reinforced by the observation that its activity is maintained after 14 days of continuous administration, making unlikely the insurgence of tolerance phenomena ( S3 Fig ); moreover, no serious adverse effects were reported in a randomized controlled pilot study with low doses of trazodone combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy [ 50 ].…”

PK/PD analysis of trazodone and gabapentin in neuropathic pain rodent models: Translational PK‐PD modeling from nonclinical to clinical development

“…The data obtained suggest that trazodone, like other basic substances, is metabolized mainly by oxidation and hydrolysis reactions; moreover, the metabolic pathway of trazodone is similar in all the animal species studied and humans. 20 The results of simulations are summarized in 2.17 (0.5, 1, 5, and 10 mg trazodone; 50 and 100 mg gabapentin), devoid of efficacy in the PD model as single agents and far below the dosages commonly used in clinical practice, 21,22 showed an enhanced effect when co-administered.…”

“…The results of simulations are summarized in Table 6 (PD results), indicating that low doses of both compounds (0.5, 1, 5, and 10 mg trazodone; 50 and 100 mg gabapentin), devoid of efficacy in the PD model as single agents and far below the dosages commonly used in clinical practice, 21 , 22 showed an enhanced effect when co‐administered.…”

Effects of gabapentin and trazodone on electroretinographic responses in clinically normal dogs

“…Humans treated with gabapentin had clinical pain improvement and had a trend toward improved pain control with the addition of trazodone, suggesting a possible synergistic mechanism. 21 Intraocular pressure and PD were measured to control for possible effects on ERG results and effects of treatments. There was no change in IOP with dilation or administration of any of the study treatments.…”