Utilization of Intravenous Lidocaine Infusion for the Treatment of Refractory Chronic Pain

Context: Chronic pain accounts for one of the most common reasons patients seek medical care. The financial burden of chronic pain on health care is seen by direct financial cost and resource utilization. Many risk factors may contribute to chronic pain, but there is no definite risk. Managing chronic pain is a balance between maximally alleviating symptoms by utilizing a therapeutic regimen that is safe for long-term use. Currently, non-opioid analgesics, NSAIDs, and opioids are some of the medical treatment options, but these have numerous adverse effects and may not be the best option for long-term use. However, Lidocaine can achieve both central and peripheral analgesic effects with relatively few side effects, which may be an ideal compound for managing chronic pain. Evidence Acquisition: This is a Narrative Review. Results: Infusion of lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide), an amino-amide compound, is emerging as a promising option to fill the therapeutic void for treatment of chronic pain. Numerous studies have outlined dosing protocols for lidocaine infusion for the management of perioperative pain, outlined below. While there are slight variations in these different protocols, they all center around a similar dosing regimen to administer a bolus to reach a rapid steady state, followed by infusion for up to 72 hours to maintain the therapeutic analgesic effects. Conclusions: Lidocaine may be a promising pharmacologic solution with a low side effect profile that provides central and peripheral analgesia. Even though the multifaceted mechanism is not entirely understood yet, lidocaine may be a promising novel remedy in treating chronic pain in various conditions.

Pharmacological properties and biochemical mechanisms of μ-opioid receptor ligands might be due to different binding poses: MD studies

Background: Central and peripheral analgesia without adverse effects relies on the identification of μ-opioid agonists that are able to activate ‘basal’ antinociceptive pathways. Recently developed μ-selective benzomorphan agonists that are not antagonized by naloxone do not activate G-proteins and β-arrestins. Which pathways do μ receptors activate? How can each of them be selectively activated? What role is played by allosteric binding sites? Methodology & results: Molecular modeling studies characterize the amino acid residues involved in the interaction with various classes of endogenous and exogenous ligands and with agonists and antagonists. Conclusions: Critical binding differences between various classes of agonists with different pharmacological profiles have been identified. MML series binding poses may be relevant in the search for an antinociception agent without side effects.

Antinociceptive Activity of the Essential Oil Formulation from the Roots of Saussaura lappa Clarks

Saussurea lappa Clarke (Compositae) is well known as a medicinal plant. Its roots are traditionally used in alleviating pain and swelling. In the current research, we have evaluated the antinociceptive activity of essential oil obtained from the roots of S. lappa. In addition, the development and evaluation of a pharmaceutical-grade cream was also conducted in this study. Extraction of essential oil from the roots of the plant was performed by a steam distillation method using the Clevenger apparatus. The antinociceptive activity was assessed in Sprague Dawley rats using tail flick, hot plate, and analgesic-meter, where diclofenac was used as a standard reference analgesic agent. S. lappa showed analgesic activity in all test systems in a dose- and time-dependent manner. In addition, the formulated cream obtained from the essential oil showed very promising pharmaceutical and pharmacological properties. The analgesic activity of S. lappa may be due to its interaction with opioid receptors and involvement of peripheral analgesia. The ability of S. lappa to show both slow- and fast-onset analgesic effects suggests it could be used as a drug candidate for pain management. The current findings thus warrant further research in the development of this novel analgesic agent.

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

β-amyrin as an analgesic component of the leaves of Callistemon citrinus (Curtis) Skeels: Chemical, biological and in silico studies

The analgesic potential of the leaves of Callistemon citrinus was reported earlier but no active principle for this analgesia was explored. To identify the major analgesic metabolite(s), the leaves were extracted with methanol and fractionated into petroleum ether, carbon tetrachloride, chloroform and aqueous soluble fractions. Based on the thin layer chromatography, the carbon tetrachloride fraction was subjected to gel permeation chromatography and a compound (1) was isolated, which was characterized as β-amyrin. Compound (1) displayed significant peripheral analgesia (p < 0.05) on mice model at an oral dose 200 mg/kg body weight. It also showed noticeable anti-inflammatory membrane stabilizing activity. In silico docking study of β-amyrin with cyclooxygenase (COX)-2 showed a good binding affinity (–9.1 Kcal/mol). Virtual pharmacokinetics and toxicity studies explore its potentials as a lead molecule having no extreme lethality.

Peripheral analgesia involves cannabinoid receptors

This landmark paper by Agarwal and colleagues was published in 2007, when the exact contribution of the activation of the cannabinoid type 1 receptor (CB1) receptors expressed on the peripheral terminals of nociceptors in pain modulation was still uncertain. At that time, while it was clearly demonstrated that the central nervous system (CNS) was involved in the antinociceptive effects induced by the activation of the CB1 receptor, many strains of mice in which the gene encoding the CB1 receptor was deleted by conditional mutagenesis were used to study the specific role of these receptors in pain. Creating an ingenious model of genetically modified mice with a conditional deletion of the CB1 receptor gene exclusively in the peripheral nociceptors, Agarwal and colleagues were the first to unequivocally demonstrate the major role of this receptor in the control of pain at the peripheral level. In fact, these mutant mice lacking CB1 receptors only in sensory neurons (those expressing the sodium channel Nav1.8) have been designed to highlight that CB1 receptors on nociceptors, and not those within the CNS, constitute an important target for mediating local or systemic (but not intrathecal) cannabinoid analgesia. Overall, they have clarified the anatomical locus of cannabinoid-induced analgesia, highlighted the potential significance of peripheral CB1-mediated cannabinoid analgesia, and revealed important insights into how the peripheral endocannabinoid system works in controlling both inflammatory pain and neuropathic pain.

Analgesic Profile of the Aqueous and Methanol Extracts of Alchornea Laxiflora in Albino Mice

The study investigated the median lethal dose and the effects of the aqueous and methanol extracts of Alchornea laxiflora in three mouse models of central and peripheral analgesia, the hot plate, acetic acid-induced abdominal writhes and the tail immersion tests. This was with a view to providing information on the acute toxicity, analgesic effects and the possible mechanism of analgesia. The LD50 for the aqueous and methanol extracts of A. laxiflora in the oral route was > 1600 mg/kg respectively, and found to be safe in animals. However, the LD50 (i.p.), was found to be 400 mg/kg for the methanol extract, which was relatively toxic and > 1600 mg/kg for the aqueous extract. Mice of both sexes (n=6) weighing 18 – 22 g were used for the study, which were randomised into control and test, which summed up to eight (VIII) groups. The control group (I) received 10 % Tween 80 (vehicle), 0.1 ml/10 g mouse while the test groups (II,III,IV,V,VI) were administered graded doses (100, 200, 400, 800, 1600 mg/kg, p.o.) of the extracts. The reference groups (VII,VIII) received standard drugs, Acetyl salicylic acid (10 mg/kg, i.p.) and Pethidine (10 mg/kg, i.p.). The animals were observed for their reaction to pain using different noxious stimuli (thermal and chemical). They were appropriately scored individually after observation 30 and 60 min post intraperitoneal and oral administrations of vehicle, extracts or drugs respectively. The results showed that A. laxiflora produced significant (P < 0.05) increase in the mean reaction time to pain in the hot plate and the tail immersion tests. It also produced a significant (P < 0.05) decrease in the number of abdominal writhes. The study concluded that A. laxiflora possesses analgesic activity. The mechanism of the analgesic effect was not through the opioidergic system