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The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica.

Sumracki NM, Hutchinson MR, Gentgall M, Briggs N, Williams DB, Rolan P - PLoS ONE (2012)

Bottom Line: 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.It 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.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia. nicole.sumracki@adelaide.edu.au

ABSTRACT

Background: Patients 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.

Aim: This 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/results: Eighteen 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.

Conclusions: It 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.

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Capsaicin-induced spontaneous pain, flare, hyperalgesia and allodynia.Time course of capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia responses following placebo (•), single oral dose minocycline (400 mg ▪) and single oral dose pregabalin (300 mg ▴) in patients with unilateral sciatica in their affected (A, C, E, G) and unaffected (B, D, F, H) leg. Data presented as mean ± SEM.
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pone-0038525-g001: Capsaicin-induced spontaneous pain, flare, hyperalgesia and allodynia.Time course of capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia responses following placebo (•), single oral dose minocycline (400 mg ▪) and single oral dose pregabalin (300 mg ▴) in patients with unilateral sciatica in their affected (A, C, E, G) and unaffected (B, D, F, H) leg. Data presented as mean ± SEM.

Mentions: Effect-time profiles are shown in Figure 1 panels A (affected leg) and B (unaffected leg). Baseline values of pain in the placebo group were 13 mm (95% CI 1 mm to 25 mm) in the affected leg, indicating a low baseline level of symptoms, and 4 mm (95% CI −0.1 mm to 9 mm) in the unaffected, confirming the largely unilateral nature of symptoms. The effect-time profiles for the VAS scores following capsaicin in both the affected leg and unaffected leg were similar, with the peak response occurring at t = 5 min, followed by a gradual decline over time. The AUC (see table 2 for all AUC values) of VAS scores was 28% (95% CI 8% to 43%) lower in the unaffected leg compared to the affected leg. However, once adjusting for multiple comparisons, statistical significance was lost (p>0.05). Neither pregabalin nor minocycline reduced the AUC of VAS scores in either the affected or unaffected leg (p>0.05). A one-way RM ANOVA demonstrated that the 10 µg dose of intradermal capsaicin used caused a significant increase in pain from baseline at t = 5 min (23 mm increase, 95% CI for increase 13 mm to 34 mm) in the affected leg [F (5, 18) = 16.61, p<0.0001] and at t = 5 min (25 mm increase, 95% CI for increase 17 mm to 34 mm) and t = 20 min (11 mm increase, 95% CI for increase 2 mm to 19 mm) in the unaffected leg [F (5, 18) = 21.23, p<0.0001] when placebo was administered, demonstrating intradermal capsaicin’s ability to induce a level of spontaneous pain that is generally considered at the lower end of clinically significant pain (∼40 mm).


The effects of pregabalin and the glial attenuator minocycline on the response to intradermal capsaicin in patients with unilateral sciatica.

Sumracki NM, Hutchinson MR, Gentgall M, Briggs N, Williams DB, Rolan P - PLoS ONE (2012)

Capsaicin-induced spontaneous pain, flare, hyperalgesia and allodynia.Time course of capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia responses following placebo (•), single oral dose minocycline (400 mg ▪) and single oral dose pregabalin (300 mg ▴) in patients with unilateral sciatica in their affected (A, C, E, G) and unaffected (B, D, F, H) leg. Data presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369912&req=5

pone-0038525-g001: Capsaicin-induced spontaneous pain, flare, hyperalgesia and allodynia.Time course of capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia responses following placebo (•), single oral dose minocycline (400 mg ▪) and single oral dose pregabalin (300 mg ▴) in patients with unilateral sciatica in their affected (A, C, E, G) and unaffected (B, D, F, H) leg. Data presented as mean ± SEM.
Mentions: Effect-time profiles are shown in Figure 1 panels A (affected leg) and B (unaffected leg). Baseline values of pain in the placebo group were 13 mm (95% CI 1 mm to 25 mm) in the affected leg, indicating a low baseline level of symptoms, and 4 mm (95% CI −0.1 mm to 9 mm) in the unaffected, confirming the largely unilateral nature of symptoms. The effect-time profiles for the VAS scores following capsaicin in both the affected leg and unaffected leg were similar, with the peak response occurring at t = 5 min, followed by a gradual decline over time. The AUC (see table 2 for all AUC values) of VAS scores was 28% (95% CI 8% to 43%) lower in the unaffected leg compared to the affected leg. However, once adjusting for multiple comparisons, statistical significance was lost (p>0.05). Neither pregabalin nor minocycline reduced the AUC of VAS scores in either the affected or unaffected leg (p>0.05). A one-way RM ANOVA demonstrated that the 10 µg dose of intradermal capsaicin used caused a significant increase in pain from baseline at t = 5 min (23 mm increase, 95% CI for increase 13 mm to 34 mm) in the affected leg [F (5, 18) = 16.61, p<0.0001] and at t = 5 min (25 mm increase, 95% CI for increase 17 mm to 34 mm) and t = 20 min (11 mm increase, 95% CI for increase 2 mm to 19 mm) in the unaffected leg [F (5, 18) = 21.23, p<0.0001] when placebo was administered, demonstrating intradermal capsaicin’s ability to induce a level of spontaneous pain that is generally considered at the lower end of clinically significant pain (∼40 mm).

Bottom Line: 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.It 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.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia. nicole.sumracki@adelaide.edu.au

ABSTRACT

Background: Patients 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.

Aim: This 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/results: Eighteen 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.

Conclusions: It 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.

Show MeSH
Related in: MedlinePlus