Category Archives: Neuropathic Pain

Cannabidiol-rich non-psychotropic Cannabis sativa L. oils attenuate peripheral neuropathy symptoms by regulation of CB2-mediated microglial neuroinflammation

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“Neuropathic pain (NP) is a chronic disease that affects the normal quality of life of patients. To date, the therapies available are only symptomatic and they are unable to reduce the progression of the disease. Many studies reported the efficacy of Cannabis sativa L. (C. sativa) on NP, but no Δ9 -tetrahydrocannabinol (Δ9 -THC)-free extracts have been investigated in detail for this activity so far. The principal aim of this work is to investigate the potential pain-relieving effect of innovative cannabidiol-rich non-psychotropic C. sativa oils, with a high content of terpenes (K2), compared to the same extract devoid of terpenes (K1). Oral administration of K2 (25 mg kg-1 ) induced a rapid and long-lasting relief of pain hypersensitivity in a mice model of peripheral neuropathy. In spinal cord samples, K2 reduced mitogen-activated protein kinase (MAPKs) levels and neuroinflammatory factors. These effects were reverted by the administration of a CB2 antagonist (AM630), but not by a CB1 antagonist (AM251). Conversely, K1 showed a lower efficacy in the absence of CB1/CB2-mediated mechanisms. In LPS-stimulated murine microglial cells (BV2), K2 reduced microglia pro-inflammatory phenotype through the downregulation of histone deacetylase 1 (HDAC-1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IKBα) and increased interleukin-10 (IL-10) expression, an important antiinflammatory cytokine. In conclusion, these results suggested that K2 oral administration attenuated NP symptoms by reducing spinal neuroinflammation and underline the important role of the synergism between cannabinoids and terpenes.”

https://pubmed.ncbi.nlm.nih.gov/36583304/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.7710

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

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“Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. We used a cisplatin-induced model of neuropathic pain in mice to assess the effects of the cannabinoids THC and CBD alone or in varying ratios as anti-nociceptive agents. In addition to testing pure compounds, we also tested extracts containing high THC or CBD at the same ratios.

We found that pure CBD had little impact on mechanical hypersensitivity, whereas THC reduced mechanical hypersensitivity in both male and female mice (as has been reported in the literature). Interestingly, we found that high CBD cannabis extract, at the same CBD dose as pure CBD, was able to reduce mechanical hypersensitivity, although not to the same level as high THC extract. These data suggest that, at least for CBD-dominant cannabis extracts, there is an increase in the anti-nociceptive activity that may be attributed to other constitutes of the plant.

We also found that high THC extract or pure THC is the most efficacious treatment for reducing neuropathic pain in this model.”

https://pubmed.ncbi.nlm.nih.gov/36289810/

https://www.mdpi.com/2227-9059/10/10/2548/htm

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences

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Experimental Neurology

“Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.”

https://pubmed.ncbi.nlm.nih.gov/36179876/

https://www.sciencedirect.com/science/article/abs/pii/S0014488622002576?via%3Dihub

Cannabidiol and Delta-9-Tetrahydrocannabinol Interactions in Male and Female Rats with Persistent Inflammatory Pain

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The Journal of Pain

“Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), two of the primary constituents of cannabis, are used by some individuals to self-treat chronic pain. It is unclear whether the pain-relieving effects of CBD alone and in combination with THC are consistent across genders and among types of pain.

The present study compared the effects of CBD and THC given alone and in combination in male and female rats with Complete Freund’s adjuvant-induced inflammatory pain.

After induction of hindpaw inflammation, vehicle, CBD (0.05-2.5 mg/kg), THC (0.05-2.0 mg/kg), or a CBD:THC combination (3:1, 1:1, or 1:3 dose ratio) was administered i.p. twice daily for three days. Then on day four, mechanical allodynia, thermal hyperalgesia, weight-bearing, and locomotor activity were assessed 0.5-4 h after administration of the same dose combination. Hindpaw edema and open field (anxiety-like) behaviors were measured thereafter.

THC alone was anti-allodynic and anti-hyperalgesic, and decreased paw thickness, locomotion, and open field behaviors. CBD alone was anti-allodynic and anti-hyperalgesic. When combined with THC, CBD tended to decrease THC effects on pain-related behaviors and exacerbate THC-induced anxiety-like behaviors, particularly in females.

These results suggest that at the doses tested, CBD-THC combinations may be less beneficial than THC alone for the treatment of chronic inflammatory pain.

PERSPECTIVE: The present study compared CBD and THC effects alone and in combination in male and female rats with persistent inflammatory pain. This study could help clinicians who prescribe cannabis-based medicines for inflammatory pain conditions determine which cannabis constituents may be most beneficial.”

https://pubmed.ncbi.nlm.nih.gov/36122809/

“THC and CBD each reduced chronic inflammatory pain (allodynia and hyperalgesia) in rats.”

https://www.jpain.org/article/S1526-5900(22)00392-3/fulltext

[Cannabinoids for the treatment of chronic pain – an overview of current medical knowledge]

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“Cannabis has been used in medicine for thousands of years, yet its use for therapeutic purposes is still controversial. Meta-analysis of the literature has shown the effectiveness of cannabinoids only in some diseases. Researchers are particularly interested in their use in chronic pain management, which analgesic effect has been proved in many studies. A review of the literature indicates that cannabinoid preparations may be effective in the treatment of some chronic pain disorders, particularly in neuropathic pain, and should be considered as a possible therapeutic choice in the absence of a satisfactory analgesic effect with standard medications. The increasing number of countries approving cannabinoids for medical use creates an opportunity to conduct more clinical trials and collect better-quality data necessary to establish clear guidelines and consistent recommendations for specific pain disorders.”

https://pubmed.ncbi.nlm.nih.gov/36086988/

Cannabidiol attenuates hypersensitivity and oxidative stress after traumatic spinal cord injury in rats

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Neuroscience Letters

“Neuropathic pain (NP) arises as a direct consequence of traumatic spinal cord injury (SCI), which leads to devastating consequences for people suffering from this condition since no specific treatment has been defined. One relevant mechanism in generating painful stimuli involves the direct participation of reactive oxygen species (ROS) at the cellular and subcellular levels.

Cannabidiol (CBD) is one of the two most crucial cannabinoid components of the cannabis plant and has been proposed as a potential treatment for NP. Its antioxidant, neuroprotective and anti-inflammatory properties have been documented. However, there is insufficient evidence regarding CBD as treatment of NP induced by SCI or the mechanisms that underlie this effect.

In this study, we evaluated the antinociceptive effect of CBD as an acute treatment after the nociceptive behaviors characteristic of NP were established (hypersensitivity threshold and hypersensitivity response). Furthermore, the participation of oxidative stress was determined by lipid peroxidation (LP) and glutathione concentration (GSH) in female Wistar rats with SCI.

Acute treatment with CBD (2.5-20 mg/kg, i.p.) decreased nociceptive behaviors in a dose-dependent manner, decreased LP, and increased GSH concentration in injured tissue 15 days after injury. The findings of this study suggest that the antinociceptive effect induced by CBD is regulated by reducing oxidative stress by decreasing the LP and increasing the concentration of antioxidant (GSH) defenses.”

https://pubmed.ncbi.nlm.nih.gov/36028005/

“Cannabidiol decreases hyperalgesia in a dose–response manner after spinal cord injury.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394022004165?via%3Dihub

Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model

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Behavioural Brain Research

“Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats.

Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6 to 9 days after surgery). Treatment with morphine (2 and 4mg/kg) or CBD (30mg/kg) induced a significant antinociceptive effect on evoked pain.

The combination of CBD (30mg/kg) and morphine (1mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1mg/Kg). Treatment with morphine (1 and 2mg/kg) or CBD (30mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30mg/kg) and morphine (1mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance.

In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.”

https://pubmed.ncbi.nlm.nih.gov/36028000/

“Taken together, the present results demonstrate that CBD or morphine exert antinociceptive effects in both mechanically evoked pain and ongoing pain after CCI in rats. The treatment combination of CBD and a sub-therapeutic dose of morphine, provided marked antinociceptive effects in both evoked and ongoing pain.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432822003448?via%3Dihub

Cannabinoids Lead to Significant Improvement in Gastroparesis—Related Abdominal Pain

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“Neuropathy plays a large role in the pathogenesis of gastroparesis. Neuropathic pain in gastroparesis is an often difficult—to—treat symptom of the disease, despite 80—90% of patients with gastroparesis reporting abdominal pain as a symptom. Treatment for gastroparesis—related pain is especially limited. Neuromodulators are used for this purpose despite a lack of evidence supporting their effectiveness.

Cannabinoids, primarily delta—9—tetrahydrocannabinol (THC) and cannabidiol (CBD), are increasingly utilized for medicinal purposes. In New York medical marijuana is approved for the treatment of neuropathy with severe pain. Similarly, Dronabinol (a synthetic THC analogue) has been used for nausea vomiting and anorexia for years.

We showed that cannabinoids are effective in the treatment of gastroparesis—related abdominal pain.”

“Conclusion: Our study shows that cannabinoids may play an important role in the management of gastroparesis—related abdominal pain. There are currently no treatments shown to be effective for gastroparetic pain in clinical trials, and cannabinoids may serve a niche for this under—treated symptom.”

https://journals.lww.com/ajg/fulltext/2018/10001/cannabinoids_lead_to_significant_improvement_in.1204.aspx

Medical Cannabis Certification Is Associated With Decreased Opiate Use in Patients With Chronic Pain: A Retrospective Cohort Study in Delaware

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Cureus Competition Winners Announced - Synaptive Medical

“Opioid medications are commonly used to treat chronic pain around the world. While these medications are quite effective at reducing pain, they can create opioid dependence and lead to further drug addiction. Long-term opioid use has significantly contributed to the “opioid epidemic” that is currently ravaging the United States, leading to opioid overdoses and unintentional deaths, particularly in Delaware.

Objective To determine if medical marijuana certification helps patients in Delaware with chronic pain reduce their opiate use.

Methods In this study, we examined individuals who were provided with legal; medical cannabis certifications in the state of Delaware between June 2018 and October 2019 and were concurrently being treated with opioid medications for chronic pain at a private pain management practice. Using a posthoc analysis, we conducted a retrospective cohort study on the individuals (n = 81) to determine if there was a decrease in their opioid use following medical cannabis certification. Opioid use was measured in morphine milligram equivalent (MME) through the Delaware prescription monitoring program (PMP) database.

Results Overall, the average change in prescribed opioid use was found to be -12.3 morphine milligram equivalent (MME) units when including all individuals (p < 0.00001). Among the included individuals with baseline opioid use, medical cannabis certification was associated with a 31.3% average decrease in opioid use (n = 63). When examining subgroups based upon pain location, individuals with neck pain displayed a 41.5% average decrease in MME (n = 27), while individuals with low back pain were observed to have a 29.4% decrease in opioid use (n = 58). Similarly, individuals with knee pain (n = 14) reduced their opioid use by 32.6%.

Conclusion The results display an association between medical cannabis certification and a decrease in opiate use among the study group individuals. This study suggests that medical cannabis use may help individuals to reduce their opiate requirements along with physician intervention. More research is needed to validate these findings with appropriate controls and verification of cannabis use.”

https://pubmed.ncbi.nlm.nih.gov/35004055/

“The results of this study indicate that medical marijuana certification is associated with a decrease in prescription opiate use for chronic pain treatment and supports greater use of this adjunct treatment modality. Given the significance of opioid addiction in American society, any treatment or additional resource to reduce opioid overuse can aid in the multifactorial management of chronic pain. Although marijuana use causes a variety of side effects, the findings here suggest that the use of medical cannabis as an adjunct treatment for chronic pain may be beneficial to public health.”

https://www.cureus.com/articles/77114-medical-cannabis-certification-is-associated-with-decreased-opiate-use-in-patients-with-chronic-pain-a-retrospective-cohort-study-in-delaware

Treatments perceived to be helpful for neuropathic pain after traumatic spinal cord injury: A multicenter cross-sectional survey study

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“Objective: To evaluate the perceived helpfulness of pharmacological and non-pharmacological interventions and their combinations for neuropathic pain (NeuP) and subcategories of NeuP after spinal cord injury (SCI).

Methods: Three hundred ninety one individuals at least one year post traumatic SCI were enrolled. A telephone survey was conducted to determine the pharmacologic and non-pharmacologic treatments used in the last 12 months for each participant’s three worst pains, whether these treatments were “helpful”, and if currently used, each treatments’ effectiveness.

Results: Two hundred twenty participants (56%) reported 354 distinct NeuPs. Pharmacological treatments rated helpful for NeuP were non-tramadol opioids (opioids were helpful for 86% of opioid treated NeuPs), cannabinoids (83%), and anti-epileptics (79%). Non-pharmacological treatments rated helpful for NeuP were massage (76%), body position adjustment (74%), and relaxation therapy (70%). Those who used both opioids and exercise reported greater NeuP treatment helpfulness compared to participants using opioids without exercise (P = 0.03).

Conclusions: Opioids, cannabinoids, and massage were reported more commonly as helpful than treatments recommended as first-line therapies by current clinical practice guidelines (CPGs) for NeuP after SCI (antiepileptics and antidepressants). Individuals with SCI likely value the modulating effects of pharmacological and non-pharmacological treatments on the affective components of pain in addition to the sensory components of pain when appraising treatment helpfulness.”

https://pubmed.ncbi.nlm.nih.gov/35993799/

https://www.tandfonline.com/doi/full/10.1080/10790268.2022.2108665?scroll=top&needAccess=true