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Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.
Learn More >To examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS).
Learn More >Paclitaxel use in cancer treatment is limited by a painful syndrome that has no effective treatment. Despite new therapies, drugs of the World Health Organization (WHO) analgesic ladder remain a useful therapeutic tool for cancer pain relief. Since cancer pain is caused by both tumor and chemotherapy, we assessed the efficacy of drugs from the WHO analgesic ladder for cancer pain relief in a paclitaxel-induced pain syndrome (P-IPS) model. P-IPS was induced in rats by one or four injections of paclitaxel on alternate days. The acute and chronic phases were assessed 24 h and 15 days after the first paclitaxel injection, respectively. The mechanical allodynia was evaluated after (step 1 of the ladder) paracetamol, (step 2) codeine alone or plus paracetamol and (step 3) morphine treatment in the acute or chronic phase of P-IPS. Paracetamol, codeine and morphine were equally efficacious in reducing the acute phase of the P-IPS. Codeine plus paracetamol had similar efficacy and potency when administered together in the acute phase of the P-IPS, but produced a longer-lasting effect than when separately managed. Moreover, paracetamol, codeine and morphine partially reduced the chronic phase of P-IPS, losing their efficacy and, in the case of codeine, potency when compared to the acute phase. However, paracetamol plus codeine increased the potency and efficacy of the codeine when compared to codeine administered alone in the chronic phase of P-IPS, producing a long-lasting anti-allodynic effect. Together, analgesics of WHO analgesic ladder reduce both acute and chronic phases of P-IPS, with codeine plus paracetamol presenting more potent, efficacious and long-lasting effect. Thus, in addition to tumor pain, drugs of WHO analgesics ladder could also be useful to treat P-IPS.
Learn More >We aimed to assess the efficacy and safety of erenumab, a fully human monoclonal antibody inhibiting the calcitonin gene-related peptide receptor (CGRPr), for the prevention of migraine in a real-life setting.
Learn More >A major challenge in medicine is developing potent pain therapies without the adverse effects of opiates. Neuroinflammation and in particular microglial activation have been shown to contribute to these effects. However, the implication of the microglial mu opioid receptor (MOR) is not known. We developed a novel conditional knockout (cKO) mouse line, wherein MOR is deleted in microglia. Morphine analgesic tolerance was delayed in both sexes in cKO mice in the hot plate assay. Opioid-induced hyperalgesia (OIH) as measured in the tail immersion assay was abolished in male cKO mice, and physical dependence to morphine as assessed by naloxone-induced withdrawal was attenuated in female cKO mice. Our results show a sex-dependent contribution of microglial MOR in morphine analgesic tolerance, OIH, and physical dependence. In conclusion, our data suggest that blockade of microglial MOR could represent a therapeutic target for opiate analgesia without the opiate adverse effects.
Learn More >The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol [Δ-THC]) enhance the analgesic effects of µ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.
Learn More >Chronic pain conditions such as neuropathic pain and persistent inflammatory pain are difficult to manage. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate nociceptive processing at the spinal dorsal horn. Previous studies have shown that intrathecal AMPA receptor antagonists exert antinociception in various pain states. Perampanel is a selective, noncompetitive inhibitor of the AMPA receptor and used clinically as an antiepileptic drug. Little is known about antinociceptive action of perampanel in the spinal cord. Here, we explored whether intrathecal perampanel attenuates neuropathic and inflammatory pain. A chronic constriction injury (CCI) to the sciatic nerve was induced in male Sprague-Dawley rats. We evaluated the effects of intrathecal perampanel (10, 30, or 100 μg) on mechanical and cold hyperalgesia using the electronic von Frey and cold plate tests, respectively. Normal rats were assessed in terms of inflammatory nociception using the formalin test, and motor function employing the rotarod test. In the CCI rats, spinally applied perampanel inhibited mechanical and cold hyperalgesia dose-dependently. In normal rats, perampanel remarkably suppressed the early- and late-phase responses in the formalin test, and it weakly affected motor performance for a short period at the highest dose. These results suggest that perampanel exerts antinociceptive actions on neuropathic and persistent inflammatory pain in the spinal cord. Perampanel may be safe and beneficial remedy for patients with such pain conditions. In addition, AMPA receptor can be a promising target for treatment of chronic pain.
Learn More >Migraine is the second leading cause of years lived with disability after back pain. Poor tolerability, contraindications, drug-drug interactions and efficacy limited to a subpopulation make new approaches necessary for the acute and preventive treatment of migraine. The study of the calcitonin-gene-related peptide (CGRP) pathway over the last decades is a good example of translational medicine leading to directed therapies for patients.
Learn More >IntroductionCurrent treatment options for the prevention of cluster headache are largely unsatisfactory. The therapies have a limited evidence base and often significant side effects issues. The involvement of the calcitonin gene-related peptide (CGRP) pathway in primary headache disorders, especially migraine, had led to recent success in the development of new migraine therapies. The CGRP pathway also plays a role in the pathophysiology of cluster headache, so CGRP pathway monoclonal antibodies have been studied in the prevention of cluster headache attacks.Areas coveredThis review will outline the trials of fremanezumab and galcanezumab, the only two CGRP pathway monoclonal antibodies that have undergone trials in cluster headache prevention thus far. This review will highlight key efficacy and safety outcomes from the trials.Expert opinionGalcanezumab was shown to be efficacious in reducing the frequency of attacks in episodic cluster headache, while fremanezumab failed its primary endpoint in episodic cluster headache. Both fremanezumab and galcanezumab trials in chronic cluster headache were terminated after futility analysis predicting failure of both trials to fulfil their primary endpoint. The role of CGRP in cluster headache supports ongoing trials of the remaining CGRP pathway monoclonal antibodies and gepants for preventive and acute treatment.A Panglossian view would include targeting neuropeptides involved in parasympathetic signalling in cluster headache, such as pituitary adenylate cyclase-activating peptide (PACAP); such targets warrant exploration in the search of new cluster headache treatments.
Learn More >Effective acute pain management has evolved considerably in recent years and is a primary area of focus in attempts to defend against the opioid epidemic. Persistent postsurgical pain (PPP) has an incidence of up to 30-50% and has negative outcome of quality of life and negative burden on individuals, family, and society. The 2016 American Society of Anesthesiologists (ASA) guidelines states that enhanced recovery after surgery (ERAS) forms an integral part of Perioperative Surgical Home (PSH) and is now recommended to use a multimodal opioid-sparing approach for management of postoperative pain. As such, dexmedetomidine is now being used as part of ERAS protocols along with regional nerve blocks and other medications, to create a satisfactory postoperative outcome with reduced opioid consumption in the Post anesthesia care unit (PACU).
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