The Effects of Pregabalin and the Glial Attenuator Minocycline on the Response to Intradermal Capsaicin in Patients with Unilateral Sciatica

Abstract

BackgroundPatients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes.AimThis study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg.Methods/ResultsEighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (−38% in affected leg, 95% CI for difference −19% to −52%). Both hand dominance and sex were significant covariates of response to capsaicin.ConclusionsIt cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain.

Pathological pain and the neuroimmune interface

“…A recent study showed that minocycline attenuated hyperalgesia in a small cohort of patients with sciatica 128 . Ibudilast also showed signs of efficacy in relieving pain associated with painful diabetic neuropathy and complex regional pain syndrome 126 .…”

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Minocycline has also shown promise in studies of pain, particularly in an animal model of morphine effects. Though minocycline has nonselective actions at both neuronal and glial cell types within the nervous system [219], its anti-inflammatory actions are theorized to be a result of its inhibitory influence on the latter [220,221]. Studies have shown this tetracycline antibiotic microglial inhibitor to reduce negative aspects of morphine treatment (respiratory depression, tolerance, and reward) while augmenting analgesia [213,222].…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Furthermore, minocycline has been shown to be beneficial in pain states such as rheumatoid arthritis (Langevitz et al, 2000) and sciatica (Sumracki et al, 2012). Both systemic and central administration of minocycline has been shown to prevent microglial activation and release of pro-inflammatory cytokines/mediators, and consequently the development of nerve injury-induced allodynia in several models (Raghavendra et al, 2003, Zanjani et al, 2006, Guasti et al, 2009, Pu et al, 2013, LeBlanc et al, 2011, Wei et al, 2008.…”