Efficacy of topical cannabinoids in the management of pain: a systematic review and meta-analysis of animal studies

Background/importanceCannabinoids are emerging as an alternative pain management option, preliminarily supported by preclinical and clinical studies. Unwanted side effects from oral or inhaled cannabinoids remain, however, a major barrier to widespread use. Peripherally acting cannabinoids (eg, topically applied) may circumvent these side effects while providing localized pain management.ObjectiveOur purpose was to systematically review the literature on the effectiveness of peripherally acting cannabinoids for pain management.Evidence reviewWe searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PubMed databases. Included studies examined the effect of topical/peripherally administered cannabinoids on pain ratings in humans, as well as pain-related outcomes in animals (eg, paw withdrawal). Due to a lack of trials, human studies were summarized in a narrative synthesis. Separate meta-analyses were performed for animal studies using radiant tail flick or paw withdrawal outcomes.FindingsOur search yielded 1182 studies following removal of duplicates, with 46 studies (6 human, 40 animal) included. Human studies (one randomized controlled trial and five case studies/series) reported no adverse events to topical cannabinoids and preliminary evidence of decreased pain ratings. Animal studies reporting tail flick (5) (2.81, 95% CI 1.93 to 3.69, p<0.001) and mechanical withdrawal (11) (2.74, 95% CI 1.82 to 3.67, p<0.001) reported prolonged responses (analgesia) in peripheral cannabinoid groups compared with controls.ConclusionsPreclinical animal studies provided low-quality evidence for peripherally administered cannabinoids to provide regional, antinociceptive effects. The scarcity of high-quality human studies underscores the need to translate preclinical evidence into well-controlled human trials.

Antioxidant, Analgesic and CNS Depressant Activities of Commelina diffusa Burm. f.

Commelina diffusa Burm. f. is a member of Commelinaceae family, which is widely grown in crop land and treated as a weed. This plant has several important medicinal properties which have not been studied extensively. In this study, the crude powder of C. diffusa whole plant was extracted with 95% ethanol and different solvent fractions (n-hexane, chloroform and methanol) were prepared from the crude extract by solvent-solvent partitioning. All these plant samples were subjected to bioassays for evaluating the antioxidant, central analgesic, peripheral analgesic and CNS depressant activities. The crude extract and its methanol soluble fraction showed mild free DPPH scavenging property with IC50 values of 98.49- and 84.77-μg/ml, respectively as compared to the standard ascorbic acid (IC50 = 2.67 μg/ml). In the analgesic activity test, the n-hexane fraction of C. diffusa at doses of 200- and 400-mg/kg body weight exhibited significant (p<0.05) central analgesic activity (tail flick test) in mice. Similarly, all the test samples showed statistically significant (p<0.05) reduction in abdominal writhing induced by acetic acid. C. diffusa showed significant CNS depressant activity which was measured by ‘open field test’ and ‘hole cross test’. Considering the potential bioactivities, the plant materials can be further studied elaborately to explore the activities of the purified compounds to aid in future drug development. Dhaka Univ. J. Pharm. Sci. 20(2): 159-166, 2021 (December)

Phytochemical & Pharmacological Investigation of Stems of Passiflora foetida

Aims: To carry out extraction, preliminary phytochemical analysis and invivo analgesic screening of extract of the stem of Passiflora foetida L. Methodology: Passiflora foetida L; Family: Passifloraceae, is an exotic fast-growing perennial and medicinal vine occurring in Germany, France and other European countries and USA and grown in different parts of India. Dried stems of Passiflora foetida L was coarsely powdered and maceration was done using Soxhlet apparatus. The ethanolic extract of stems of Passiflora foetida L was subjected to preliminary phytochemical tests. Then subjected to in vivo analgesic activity. Results: Phytochemical investigation of the stem of Passiflora foetida L preliminary test showed the presence of carbohydrates, glycosides, flavonoids and steroids. Acute toxicity study of ethanolic extract of stems of Passiflora foetida L was carried out and extracts were found to be safe up to 2000 mg/kg body weight. Pharmacological activities of stems of Passiflora foetida L was carried out from ethanolic extract. Conclusion: Phytochemical investigation of ethanolic extract of stems were carried out and Analgesic activity by tail flick method in rats and acetic acid induced writhing method in mice, showed statistically significant activity (P=.05) when compared to control. The ethanolic stem extract of Passiflora foetida L proved to have significant pain relieving action in a dose dependent manner.

EXPERIMENTAL EVALUATION OF ANALGESIC ACTIVITY OF AQUEOUS EXTRACT OF TERMINALIA PANICULATA BARK IN RATS

This study was conducted to determine the analgesic activity of aqueous extract of Terminalia paniculata (Tp) bark. Analgesic activity was determined using hot plate and tail flick method. Thirty adult Wistar rats were divided into 5 groups of 6 rats each. Group I (control) received 2 mL water, Group II -codeine 5 mg kg-1, Group III, IV and V 100, 200 and 400 mg kg-1 of Tp, respectively. Latency time to pain sensation was noted. In hot plate model, group 5 showed significant increase in reaction time compared to groups 3 and 4 at all-time points and was comparable to standard codeine at 120th and 180th min. In tail flick method, standard codeine showed significant increased latency time compared to all three doses of Tp at 90th, 120th and 180th min. Group 5 showed significant increased reaction time compared to groups 3 and 4 from 60th min to 180th min. Group 4 showed increased analgesic activity compared to group 3 at 90th, 120th and 180th min but group 3 was significantly better at 30th min. Thus T. paniculata possesses analgesic potential.

Phytochemical Investigation and Analgesic Activity of Stem Bark Extract of Sapindus trifoliatus Linn

Aims: The study is designed to isolate and charecterize the phytoconstituents, and screen for the analgesic activity of stem bark extracts of Sapindus trifoliatus Linn. Methodology: The cleaned, dried and powdered stem barks of Sapindus trifoliatus were subjected to extraction by maceration process. The concentrated ethanolic extract of stem bark on was further subjected to preliminary phytochemical studies. The fractionated extracts were then packed into column chromatography for the isolation of phytoconstituents and they were characterized by IR, 1HNMR, 13CNMR and mass spectroscopy.Acute toxicity was performed to establish the lethal dose of the extract and In vivo analgesic activity was performed by tail flick and acetic acid induced writhing methods in experimental animals. Results: Preliminary phytochemical studies showed the presence of steroids, terpenoids, flavonoids, saponins and carbohydrates. Isolation of extracts led to give compounds like saponin glycoside, a steroid and triterpenoids. The extract was found to be safe up to 2000 mg kg bodyweight. Analgesic activity was found significant at level P = 05 when compared with control by tail flick and acetic acid induced writhing models in experimental animals. Conclusion: From ethanolic extract isolated a saponin glycoside,from petroleum ether stigmasterol and triterpenoids ursolic acid. The presence of saponin glycoside, triterpenoids, steroids might be responsible for the analgesic activity of the stem bark extract of Sapindus trifoliatus Linn.

Silibinin and Nano-Silibinin in Cuprizone Model of Multiple Sclerosis: Behavioral and Biochemical Investigation

Objectives: Multiple sclerosis (MS) is a long-lasting demyelinating inflammatory disease of the central nervous system (CNS). It has been shown that brain tissue in MS is exposed to oxidative stress during the disease period. Silymarin, a plant-derived flavonoid, can be extracted from Silybum marianum. The current experiment aimed to explore the effects of silibinin and especially nano-silibinin on neurobehavioral activity and biochemical antioxidant parameters in the cuprizone model of demyelination in mice for the first time. Methods: Demyelination was induced in mice by oral consumption of cuprizone 0.4%w/w for one week and then 0.2%w/w for four weeks. Treatment was performed with silibinin or nano-silibinin (70mg/kg body weight) for four weeks at the same time with cuprizone 0.2%w/w. After neurobehavioral tests (rotarod, tail flick, and open field), biochemical antioxidant parameters (glutathione level, superoxide dismutase activity, lipid peroxidation products, and total antioxidant capacity) were evaluated. Results: In this experiment, behavioral tests (rotarod and open field) displayed improvement in movement dysfunction using silibinin or nano-silibinin. Furthermore, silibinin and more efficiently nano-silibinin increased antioxidant parameters, such as superoxide dismutase (SOD) and glutathione (GSH) and total antioxidant capacity (TAC), and decreased lipid peroxidation. Conclusion: These data suggest that silibinin and nano-silibinin can improve movements in the cuprizone model of demyelination. Moreover, they may prevent cuprizone-induced oxidative stress. In conclusion, silibinin and more effectively, nano-silibinin, may exhibit therapeutic features in MS disease.

Stability control of a vehicle with tire blowout based on active steering and differential braking

The vehicle with tire blowout will have dangerous working conditions such as yaw and tail flick, which will seriously endanger the safety of driving. A tire blowout model was established based on the UniTire model and the change of tire blowout mechanical characteristics. A Carsim/Simulink joint simulation platform was built to study the dynamic response of the vehicle after the front wheel tire blowout under curve driving. A combined control strategy of outer-loop trajectory control and inner-loop differential braking control based on sliding mode fuzzy control algorithms and fuzzy PID control algorithms was proposed to ensure that the vehicle can still follow the original trajectory stably after tire blowout. The results show that the tire blowout of the front wheel on the same side as the turning direction has a great influence on the instability and yaw of the vehicle, and the designed control strategy can effectively control the running track of the vehicle with tire blowout and the vehicle stability.

The Human SCN10AG1662S Point Mutation Established in Mice Impacts on Mechanical, Heat, and Cool Sensitivity

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.

Acute toxicity, anti-inflammatory, analgesic and antipyretic effects of aqueous and hydroethanolic extracts of Brenania brieyi (Rubiaceae)

Brenania brieyi (Rubiaceae) is widely used in traditional Congolese medicine in the treatment of many pathologies that are manifested by inflammation, pain and fever. The objective of this study was to study the acute toxicity as well as to evaluate the antipyretic, analgesic and anti-inflammatory effects of the aqueous and hydro-ethanolic extracts of Brenania brieyibark on models of pyrexia, algesia and inflammation induced in rodents. The aqueous extract of Brenania brieyidoes not cause any mortality up to the dose of 4000 mg/kg, but promotes a slight increase in body weight. From 2000 mg/kg, the signs of toxicity observed were the significant decrease in mobility as well as the loss of alertness. At doses of 100 and 200 mg/kg, aqueous and hydro-ethanolic Brenania brieyiextracts showed a very significant anti-inflammatory effect (***p< 0.001) on edemas induced by carrageenin (1%), formaldehyde (2.5%) and histamine (1 mg/mL), greater than that of diclofenac at 10 mg/kg. At 200 mg/kg, both extracts showed a very significant analgesic effect (***p< 0.001), greater than that of paracetamol 100 mg/kg against pain induced by acetic acid 0.6% and formaldehyde 2.5%. Brenania brieyiwas slightly effective in the tail flick test. Brewer's yeast-induced hyperthermia was reduced by both extracts. However, the hydro-ethanolic extract proves to be more effective than the aqueous extract in all the tests carried out. These pharmacological effects would be related to the presence of alkaloids, tannins, flavonoids, anthraquinones, oses and saponosides.

Analgesic activity of Hydroalcholic extract of Achyranthes aspera leaves on animal model

Achyranthes aspera L. (Family: Amaranthaceae) is widely used as a medicinal plant. The hydroalcholic extract of Achyranthes aspera L. leaves was screened for its analgesic activity. The dose (200 mg/kg) was tested for analgesic activity using hot plate and Tail flick test in albino mice. The hydroalcholic extract of Achyranthes aspera L. leaves showed maximum analgesic activity in hot plate at reaction time 120 min (7.40±0.08) and tail flick method at reaction time 120 min (6.9±0.06). These study suggest that the hydroalcholic extract of Achyranthes aspera L. could be considered as potential analgesic agent.