Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Assessment of anti-nociceptive effect of allopurinol in a neuropathic pain model.

BACKGROUND: This study aimed to investigate the antinociceptive effect of allopurinol, a xanthine oxidase inhibitor, in the chronic constriction injury (CCI) to sciatic nerve rat model of neuropathic pain. METHODS: Allopurinol administration (30, 60, 90 mg/kg, i.p.) was started at the time of nerve injury, and given for 14 continuous days. Behavioural tests (von Frey filaments, acetone drop, hot plate) were conducted on days 0, 3, 7, 10 and 14. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was performed on the spinal cord of CCI animals on day 14. The contribution of adenosine (A) receptors was tested using the methylxanthine theophylline, a non-selective A receptor antagonist and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective A1 receptor antagonist, administered 30 min before allopurinol on day 10. RESULTS: CCI of the sciatic nerve resulted in a persistent mechanical allodynia, cold allodynia, and heat hyperalgesia, together with increased iNOS, bax/bcl2, iba-1 and TNF-α expression in the lumbar spinal cord of animals. The highest-dose group of allopurinol (90 mg/kg) attenuated pain-like behaviors compared with the normal saline treated group, and this was accompanied by normalization of iNOS, bax/bcl2, caspase 3, iba-1 and TNF-α gene expression changes. DPCPX and theophylline reversed the thermal anti-hyperalgesic effect of allopurinol. In contrast, the mechanical anti-allodynic effect was only prevented by theophylline. CONCLUSION: Allopurinol through interacting with different aspects of neuropathic pain, via anti-oxidant effects, protection against neuroinflammation, and activating adenosine receptors, could be useful in the treatment of patients with neuropathic pain.

Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat.

There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect-effect pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy.

Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms.

Neuroimaging of pain: advances and future prospects.

UNLABELLED: Chronic pain conditions remain a high unmet medical need, and a significant number of patients are not effectively treated with currently available therapies. There is a significant challenge in developing more effective therapies to treat pain, particularly in chronic debilitating pain conditions such as neuropathic pain. Preclinical research has been beneficial in advancing mechanistic understanding of the pathophysiology of pain as well as in defining new therapeutic targets for intervention. However, the increased understanding of the neurobiology of pain has not yet translated into breakthroughs in pain therapies. Some debate exists as to how predictive the common animal models of pain are to the human condition. Translation animal model activity promises to be enhanced by application of novel neuroimaging technologies. It is well acknowledged throughout the industry that the application of preclinical to clinical translational biomarkers is an important strategy that holds promise in increasing the confidence in the translatability of the preclinical to clinical data. Imaging biomarkers have tremendous potential for affecting pain research from both diagnostic as well as therapeutic standpoints. Noninvasive imaging has the inherent advantage of being able to evaluate central mechanisms of pain and the effects of intervention both in animals and in humans. Because each subject serves as its own control, the inherent intersubject variabilities can be less of a confound. This review discusses both the promise and limitations of using imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Each section summarizes current clinical reports and, if applicable, preclinical translational findings. Emphasis is given to technical areas for future development and revealing neuroinflammation dynamics and targets that are influenced by genetics and cellular insults. With continued application of neuroimaging technologies, new therapeutic approaches to treat chronic pain as well as define tools to assess functional outcomes promise to emerge. PERSPECTIVE: This review discusses the promises and limitations of using noninvasive imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Emerging neuroimaging technologies may spawn new therapeutic approaches to treat chronic pain as well as define translational tools to assess functional clinical outcomes.