Pregabalin Added to Buprenorphine Shows No Pain Benefit
Key Takeaways
- In adults with chronic peripheral neuropathic pain due to polyneuropathy that persisted despite tricyclic antidepressants and/or serotonin-norepinephrine reuptake inhibitors, a randomized phase IV comparison of transdermal buprenorphine with pregabalin or placebo did not show a higher responder rate with add-on pregabalin.
- Secondary assessments of pain intensity, pain interference, neuropathic symptoms, mood, anxiety, and quality of life were similar between the combination and monotherapy groups.
- Prespecified phenotype analyses did not identify a subgroup with a clearer response advantage from adding pregabalin to transdermal buprenorphine.
- Most participants assigned to combination therapy remained at pregabalin 100 mg/day after titration rather than escalating further.
- Adverse-event frequencies were broadly similar and no serious adverse events occurred, although headache was reported in 47% of the monotherapy group and 21% of the combination group.
In Brazil, the phase IV trial was a single-center, randomized, double-blind, placebo-controlled pragmatic study at the Pain Center of the Neurology Department at Hospital das Clínicas, University of São Paulo Medical School. Eligible adults had definite chronic peripheral neuropathic pain due to polyneuropathy, a Douleur Neuropathique 4 (DN4) score of at least 4, pain for at least 3 months, an average visual analog scale (VAS) pain score of at least 4, and inadequate relief despite tricyclic antidepressants and/or serotonin-norepinephrine reuptake inhibitors. Sixty participants were enrolled; most were women and median age was 53 years. Both groups started weekly transdermal buprenorphine 5 mcg/h plus pregabalin 50 mg every 12 hours or matching placebo, then underwent 3 weeks of flexible titration and 6 weeks of maintenance while continuing baseline neuropathic pain medications without dose changes.
The primary endpoint was at least 30% reduction in average pain intensity at week 9/end of maintenance, and secondary assessments included the brief pain inventory (BPI), Neuropathic Pain Symptoms Inventory (NPSI), Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life-BREF (WHOQoL-BREF), with a modified intention-to-treat analysis using multiple imputation for missing data.
At week 9, 41% of the combination group and 39% of the monotherapy group achieved at least 30% pain reduction (OR 1.13, 95% CI 0.32–3.99; p=0.942). VAS pain intensity, BPI severity and interference, DN4, NPSI totals and subscores, HADS measures, and WHOQoL-BREF scores were otherwise similar, and prespecified phenotype analyses did not identify a response advantage for the combination. Most combination-arm participants remained at pregabalin 100 mg/day after titration, and buprenorphine doses were similar between groups. Headache was more frequent with monotherapy than with the combination (47% vs 21%, p = 0.043); seven participants discontinued because of side effects, and no serious adverse events occurred.
These findings are bounded to adults with polyneuropathy-related peripheral neuropathic pain treated at a single Brazilian center, which narrows generalizability. The authors noted that the trial was powered for a large effect, so smaller benefits could have been missed, and that the phenotype analyses may have been underpowered. Attrition was higher than planned, and the analyses depended on multiple imputation assumptions. Most participants assigned to combination therapy did not reach the minimally therapeutic pregabalin dose cited by the authors, which may have limited the ability to detect benefit. Because the comparator was buprenorphine monotherapy rather than pregabalin alone, the trial does not answer that separate treatment question. For North American readers, this Brazil-based specialty pain clinic population should not be read as direct evidence for broader U.S. practice settings.
In this trial, adding pregabalin to transdermal buprenorphine did not yield additional analgesic benefit for refractory peripheral neuropathic pain due to polyneuropathy, and no phenotype-defined subgroup advantage emerged. The combination showed limited feasibility because most participants could not titrate pregabalin beyond 100 mg/day.
Clinician Questions
Which patients with peripheral neuropathic pain were represented in this buprenorphine-pregabalin trial?
The trial represented adults aged 18 years or older with definite chronic peripheral neuropathic pain due to polyneuropathy, a Douleur Neuropathique 4 score of at least 4, pain for at least 3 months, an average visual analog scale pain score of at least 4, and inadequate relief despite tricyclic antidepressants and/or serotonin-norepinephrine reuptake inhibitors, all treated at a single Brazilian specialty pain center. The findings do not automatically extend to other neuropathic pain syndromes or to comparisons with pregabalin monotherapy.
How was treatment intensified in the buprenorphine-pregabalin comparison for refractory polyneuropathy-related neuropathic pain?
Both groups started weekly transdermal buprenorphine 5 mcg/h, and the combination arm also received pregabalin 50 mg every 12 hours. During a 3-week titration period, study-drug doses were increased as tolerated, followed by a 6-week maintenance phase while baseline neuropathic pain medications stayed unchanged.
What unanswered question did the authors highlight after the negative buprenorphine-pregabalin result?
The authors said low-to-moderate analgesic effects could not be excluded, noted that most participants in the combination arm did not reach at least 150 mg/day of pregabalin, and indicated that the trial does not answer how buprenorphine plus pregabalin compares with pregabalin monotherapy. They also noted that clinical features beyond the tested NPSI phenotypes could still matter for identifying responders.
Recommended Reading
- For more on neuropathy-related pain burden: Small Fiber Neuropathy Diagnosis Didn't Change Pain Burden
- For more on neuropathic pain recognition: Examining the Prevalence of Neuropathic Pain