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Medical marijuana is becoming widely available to patients in the U.S. and with recreational marijuana now legalized in many states, patient interest is on the rise. The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. There are numerous studies of in vitro and animal models that provide insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of both peripheral itch fibers and centrally-acting cannabinoid receptors. In addition, human studies, while limited due to differences in cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptomatology in chronic pruritus. Clinical studies that have shown reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, allergic contact dermatitis) and systemic (uremic pruritus, cholestatic pruritus) diseases. These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal.
Learn More >Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.
Learn More >Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam.
Learn More >Pituitary adenylate cyclase-activating polypeptide (PACAP) occurs as either a 27- or 38-amino acid neuropeptide and belongs to the vasoactive intestinal polypeptide/glucagon/secretin family of peptides. PACAP and vasoactive intestinal polypeptide have a 68% homology of their amino acid sequences and share three B-type G-protein coupled receptors: VPAC, VPAC and PAC receptors.
Learn More >Patellofemoral pain (PFP) is a common complaint among young sports active adolescents. This study evaluated the longitudinal changes in pronociceptive and antinociceptive mechanisms in young adolescents with PFP, their impact on prognosis, and responsiveness to treatment. Adolescents (N = 151, aged 10-14 years) diagnosed with PFP were compared with age-matched controls (N = 50) and subsequently tracked while participating in an intervention focussed on activity modification. They underwent quantitative sensory testing at baseline (preintervention), 4 weeks (during initial treatment), and 12 weeks (after treatment). Pressure pain thresholds (PPTs) were recorded on the knee, shin, and elbow. Temporal summation of pain (TSP) was assessed by the increase in pain intensity during 10 repeated cuff pressure pain stimulations on the leg. Conditioned pain modulation (CPM) was defined as change in cuff pain thresholds on one leg, during painful cuff conditioning on the contralateral leg. At baseline, adolescents with PFP had decreased PPTs at the knee, shin, and elbow (P < 0.001) as well as more facilitated TSP (P < 0.05) compared with controls. For CPM at baseline, controls displayed an increase in cuff pain thresholds during conditioning (P < 0.05), while those with PFP did not. More facilitated baseline TSP was associated with less improvements in pain intensity during the intervention (P < 0.01). Pressure pain thresholds increased at both follow-ups (P < 0.001), and the increased PPTs were associated with decreases in pain intensity (r = 0.316; P < 0.001). Overall, TSP remained facilitated at follow-ups, and there was no change in CPM. This is the first study to demonstrate a pronociceptive mechanism as a prognostic factor in young adolescents with PFP.
Learn More >Painful conditions affect a significant population in the United States. As the scientific understanding of the benefits and harms of opioid therapy has evolved, so too has the application of prescription opioid therapy for the treatment of pain. The rapid increase in the use of prescription and illicit opioids over the past decade has contributed to a public health crisis commonly referred to as the "opioid crisis." In this article, the ethical approaches to treating patients with opioid pharmaceuticals as well as the development of regulation of opioid therapy in Washington State are reviewed.
Learn More >Studies have shown a significant association between migraine and endometriosis, but no study has explored the relationship between migraine and endometriosis phenotypes: Superficial peritoneal endometriosis, ovarian endometrioma, and deep infiltrating endometriosis.
Learn More >Acute pain is a common complication after injury of a peripheral nerve but the underlying mechanism is obscure. We established a model of acute neuropathic pain via pulling a pre-implanted suture loop to transect a peripheral nerve in awake rats. The tibial (both muscular and cutaneous), gastrocnemius-soleus (muscular only), and sural nerves (cutaneous only) were each transected. Transection of the tibial and gastrocnemius-soleus nerves, but not the sural nerve immediately evoked spontaneous pain and mechanical allodynia in the skin territories innervated by the adjacent intact nerves. Evans blue extravasation and cutaneous temperature of the intact skin territory were also significantly increased. In vivo electrophysiological recordings revealed that injury of a muscular nerve induced mechanical hypersensitivity and spontaneous activity in the nociceptive C-neurons in adjacent intact nerves. Our results indicate that injury of a muscular nerve, but not a cutaneous nerve, drives acute neuropathic pain.
Learn More >Capsaicin, derived from the chilli pepper plant, is available in high concentration (8%) patches to provide topical therapy for neuropathic pain. Its analgesic effects relate to defunctionalisation and nerve terminal retraction of predominantly C fibres in the dermis and epidermis. Systematic reviews and meta-analysis support its use for the management of post-herpetic neuralgia and HIV neuropathy with some evidence for use in painful peripheral diabetic neuropathy. The article concludes with advice on the practicalities of running a topical 8% capsaicin clinic for peripheral neuropathic pain.
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