Category Archives: Chronic Pain

The Role of the Endocannabinoid System in the Mechanism of Action of Nonopioid Analgesics

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“The endocannabinoid system (eCBS) plays a crucial role in pain modulation through its components, including endocannabinoids, cannabinoid receptors (CB1 and CB2), and metabolic enzymes.

Recent research highlights the interaction between the eCBS and non-opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and pyrazolones. These agents may enhance endogenous endocannabinoid levels or influence eCBS signaling pathways, providing a multifaceted approach to pain relief.

This review examines the pharmacological mechanisms underlying these interactions, focusing on the potential of non-opioid eCBS interactions, detailing synergistic effects that could improve analgesic efficacy while minimizing side effects. Additionally, we explore the therapeutic implications of co-administering non-opioid analgesics with eCBS modulators to create more effective pain management strategies.

The combined modulation of non-opioid pathways and the eCBS represents a promising treatment for acute and chronic pain, warranting further clinical investigation and translational research in this evolving field.”

https://pubmed.ncbi.nlm.nih.gov/40659176/

“Emerging Therapeutic Strategies: The integration of non-opioid medications with eCBS modulators represents a novel approach in pain management strategies, aiming to minimize opioid use while maximizing therapeutic efficacy and safety profiles during chronic pain management.”

https://www.sciencedirect.com/science/article/abs/pii/S0014299925007009?via%3Dihub

Cannabidiol interactions with Δ-9-tetrahydrocannabinol on antinociception after carrageenan-induced inflammatory pain in male and female rats

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“Cannabis products used for pain typically contain Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) in varied amounts, but data on the effects of specific cannabinoid formulations on different pain types are lacking.

This study used the carrageenan-induced inflammatory pain model to test oral Δ9-THC, CBD, or their combination on acute edema and pain hypersensitivity.

Male and female Sprague-Dawley rats (n = 10-14 per sex/group) were pretreated (1 hour) with vehicle (sesame oil), Δ9-THC (1, 3, and 10 mg/kg, p.o.), CBD (10, 30, 100 mg/kg, p.o.), or select doses of Δ9-THC + CBD combinations prior to an intraplantar λ-carrageenan injection into the hind paw.

The nonsteroidal anti-inflammatory drug ketoprofen (10 and 20 mg/kg i.p.) or its vehicle (1:1:18 ethanol:Cremophor EL:saline [Millipor Sigma]) was administered to a separate group as a positive control. Measurements were conducted at baseline and 1, 3, and 5 hours after carrageenan injection. Carrageenan produced edema and hypersensitivity to radiant heat (hyperalgesia) and mechanical pressure (allodynia).

Δ9-THC alone sex- and dose-dependently decreased hyperalgesia and allodynia but not inflammation, with effects of Δ9-THC being greater in females than males, and the lowest Δ9-THC dose was proinflammatory in males. CBD alone did not affect pain sensitivity but had modest anti-inflammatory effects in males. Isobolographic and dose addition analyses indicated Δ9-THC + CBD was subadditive relative to Δ9-THC alone.

These data demonstrate that prophylactic oral Δ9-THC alleviates acute inflammatory pain with sex-dependent effects, and CBD diminishes Δ9-THC antinociception when combined.

The findings suggest oral Δ9-THC is superior to CBD or combined Δ9-THC + CBD for acute inflammatory pain.

SIGNIFICANCE STATEMENT: Despite the popularity of cannabis for pain management, empirical data on how specific cannabinoid formulations affect acute inflammatory pain are limited. This study in rats found that pure Δ-9-tetrahydrocannabinol (Δ9-THC) formulations were most effective at improving inflammatory pain compared to pure cannabidiol or Δ9-THC + cannabidiol combinations, and females were more sensitive than males to the antinociceptive effects of Δ9-THC.”

https://pubmed.ncbi.nlm.nih.gov/40609153/

https://jpet.aspetjournals.org/retrieve/pii/S0022356525398381

Cannabinoid receptor ligands with potential therapeutic applications and mechanisms of action: a versatile natural therapeutic agent

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“The endocannabinoid system (ECS) is a complex signaling network essential for regulating various physiological processes in the body. Selective cannabinoid receptor ligands have been developed to modulate specific ECS signaling pathways, offering potential therapeutic benefits. These ligands, with high selectivity and affinity for cannabinoid receptors, demonstrate potential in managing diverse medical conditions. Standardizing dosing is crucial to ensure reliable therapeutic effects, as cannabinoids may exhibit biphasic effects. Combination strategies involving both CB1 and CB2 receptor modulation show promise in managing complex conditions, including chronic pain, autoimmune disorders, and neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/40600897/

https://www.tandfonline.com/doi/full/10.1080/10286020.2025.2522396

How to ESCAPE from Pain? An Observational Study on Improving Pain and Quality of Life with the Cannamedical® Hybrid Cannabis Extract

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“Introduction: Chronic pain remains a challenge, with standard therapies often providing inadequate pain relief and causing undesirable side effects. Medicinal cannabis has emerged as promising alternative. This study assessed the impact of a cannabis hybrid extract on pain intensity and quality of life in daily clinical use.

Methods: ESCAPE was an observational study and included patients aged ≥ 18 years with chronic pain in Germany. The primary objective was to evaluate the effectiveness of the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 on pain during four visits (V1-V4) in clinical practice, and key secondary objectives were pain interference and quality of life. Pain intensity was measured using the Numeric Rating Scale (NRS) of the Brief Pain Inventory (BPI) questionnaire. Pain interference was evaluated with the BPI pain interference subscore, and quality of life-particularly physical and mental health-was assessed with the Short Form-12 (SF-12) questionnaire. Additionally, patient and physician satisfaction with the extract was assessed.

Results: The study included 64 patients (50% female) with chronic pain (intention-to treat population; ITT). Cannabis-naïve patients of the ITT were defined as a subgroup and analyzed separately (N = 35). Mean (± SD) NRS-assessed pain intensity decreased during the study, in both the ITT (5.46 ± 1.73 at V1 vs. 3.37 ± 2.43 at V4) and in the cannabis-naïve subgroup (5.92 ± 1.34 at V1 vs. 2.37 ± 1.69 at V4). Mean pain interference subscore decreased between V1 and V4 for the ITT (5.39 ± 1.92 vs. 3.38 ± 2.46) and the cannabis-naïve group (5.68 ± 1.46 vs. 2.54 ± 1.99). Physical and mental health improved in both groups and high satisfaction with the hybrid cannabis extract was reported by patients and physicians.

Conclusion: Treatment with the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 in daily clinical practice showed positive effects on patients’ pain and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/40560527/

https://link.springer.com/article/10.1007/s12325-025-03262-z

Effectiveness of Full Spectrum Cannabis Extracts in the Treatment of Chronic Pain: An Open Label Study

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“The aim of this work was to assess the effectiveness of full-spectrum cannabis (THC and CBD) extracts as adjuvants in the treatment of chronic pain. This is a prospective, open label, longitudinal study.

Major cannabinoids were analyzed in herbal preparations using high performance liquid chromatography (HPLC). Subjects were included when chronic pain diagnosis criteria was met according to physicians’ diagnosis. A patient stratification protocol was developed using a visual analogue scale to measure pain, a numerical scale for life quality parameters and a self-administered health survey. Eighty-eight patients aged between 35 and 88 years were included.

A significant decrease in both pain and other life quality parameters was observed between time zero and subsequent time intervals, excepting the “appetite” variable.

Overall, 51 individuals reported a decrease in pain, 38 a decrease in anxiety and 48 in insomnia, with “decrease” defined as symptom reduction of 50% or more between the first and last consultation. In addition, 23 subjects reduced or discontinued other analgesics and/or anti-inflammatory drugs during the trial. Adverse effects were mild and reversible.

These results are consistent with previous studies, supporting effectiveness and safety of cannabis extracts as adjuvants in the treatment of chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/40526158/

https://www.tandfonline.com/doi/full/10.1080/15360288.2025.2517778

Patterns, Efficacy, and Cognitive Effects of Medical Cannabis Use in Chronic Musculoskeletal Pain Patients

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“Background: Medical cannabis (MC) is being used with greater frequency in the management of chronic pain. While its efficacy in pain relief is promising, questions about patterns of use and efficacy warrant further investigation. This study aimed to evaluate long-term MC use patterns, perceived efficacy, and its impact on cognition among patients with chronic musculoskeletal noncancer pain.

Methods: This prospective study included patients who were certified for MC between October 2022 and December 2024. Patients who were certified for MC under Pennsylvania state guidelines for a minimum of one year were tracked, yielding 129 patients for analysis. The patients completed an Inventory of Medical Cannabis Use (IMCU) questionnaire assessing usage patterns, dosage knowledge, efficacy, cognitive effects, and tolerance changes. The responses were collected in a password-protected database.

Results: A total of 77.5% of patients reported using MC daily or near daily. Topical formulations were most frequently used (63.6%). Approximately half of the respondents were uncertain of their exact tetrahydrocannabinol/cannabidiol (THC/CBD) dosage, with a median oral dose of 10 mg recorded among those who provided estimates. High levels of perceived efficacy were reported, with over 93% of respondents agreeing or strongly agreeing that MC improved their primary symptoms. Cognitive and motor effects were minimal for most users, with 72.1% reporting no impact. Furthermore, 79.8% of respondents indicated stable usage patterns over the prior three months, and very few reported a need or external suggestion to reduce MC intake.

Conclusions: Long-term MC use is a stable and well-tolerated option for managing chronic musculoskeletal pain, with high patient-reported efficacy and minimal cognitive impact. These findings support its role in pain management while highlighting the need for further research on optimal dosing and long-term safety.”

https://pubmed.ncbi.nlm.nih.gov/40519367/

https://www.cureus.com/articles/365077-patterns-efficacy-and-cognitive-effects-of-medical-cannabis-use-in-chronic-musculoskeletal-pain-patients#!/

New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity

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“Inflammation is the organism’s protective mechanism to restore cellular and tissue homeostasis. Cannabidiol has been reported for its ability to bind to diverse receptors related to or not related to the endocannabinoid system, with good safety being one of the most promising phytocannabinoids for therapeutical purposes. CBD has shown in vitro and in vivo ability to significantly reduce the production of cytokines and other inflammatory mediators, with an unclear mechanism of action.

Herein, we report the design and synthesis of a novel series of eight terpene N-acylaryl hydrazone analogues and their pharmacological evaluation for potential antioxidant, antinociceptive, and anti-inflammatory properties.

Our results led to the identification of compounds 5a (PQM-242), with significant peripheral and central antinociceptive effects, 5b (PQM-243), and 5g (PQM-248) with antinociceptive activities probably related to the ability of modulation of TRPV1 receptors, and 5c (PQM-244) that seems to have the most promising peripheral antinociceptive profile, showing significant effects on both neurogenic and inflammatory phases of formalin-induced licking test, coupled to potential antioxidant activity.

Overall, our experimental data suggest that the new CBD-based architecture is capable of ensuring peripheral and central antinociceptive effects by different modes of action, with no in vivo toxicity and adequate predicted ADME properties.”

https://pubmed.ncbi.nlm.nih.gov/40521634/

“Several compounds showed similar antinociceptive and anti-inflammatory effects to those described for CBD.”

https://www.tandfonline.com/doi/full/10.1080/17568919.2025.2515821

Combination of Cannabidiol and Low-Dose Buprenorphine Suggests Synergistic Analgesia and Attenuates Buprenorphine-Induced Respiratory Depression

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“Introduction: As opioid-related drug overdoses remain a public health crisis, there is a critical need for innovative approaches to developing safer analgesics with improved safety profiles. BDH-001 is a fixed-dose combination of low-dose buprenorphine (BUP) and cannabidiol (CBD) being developed as a safer analgesic than currently available opioids. The purpose of this study was to examine the analgesic and opioid-sparing effects of BDH-001 and to complete an in vivo safety assessment in rats. 

Methods: Analgesic effect of BDH-001 was assessed using the chronic constriction injury model of chronic neuropathic pain with pain threshold assessed via Von Frey testing. Drug-drug interaction effects on pharmacokinetic (PK) parameters were assessed in a single dose PK study in rodents. The effects on respiratory depression were also assessed and confirmed in two separate rodent studies performing blood gas analysis and measuring O2 saturation. 

Results: BDH-001 (combination of subanalgesic BUP dose and CBD) resulted in statistically significant increases in pain threshold compared to saline (p < 0.001), CBD alone (p < 0.01), and BUP alone (p < 0.05). The half-life of BUP was significantly shorter in the presence of CBD compared to BUP alone (p = 0.008), with no significant changes in any other BUP pharmacokinetic parameter assessed. CBD was found to attenuate BUP-induced respiratory depression in rats when assessing blood gases (p < 0.05) and O2 saturation (p < 0.05) over several time bins. 

Conclusions: Data obtained in the present study indicate the addition of CBD to BUP was opioid-sparing and attenuated BUP- but not morphine-induced respiratory depression. There was no evidence these findings were the result of a PK interaction. Results support the hypothesis that BDH-001, a fixed-dose combination of BUP and CBD, may provide effective analgesia with a more favorable safety profile.”

https://pubmed.ncbi.nlm.nih.gov/40468945/

https://www.liebertpub.com/doi/10.1089/can.2025.0004

“Buprenorphine is a medication that plays a crucial role in treating opioid use disorder (OUD), also known as opioid addiction. It works by partially activating the same receptors in the brain as opioids, helping to reduce withdrawal symptoms and cravings without producing the intense euphoria or dangerous side effects associated with full opioid agonists like heroin or fentanyl.”

Effects of combined CBGA and cannabis-derived terpene nanoformulations on TRPV1 activation: Implications for enhanced pain management

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“Cannabinoids and terpenes, key bioactive components of cannabis, are increasingly studied for their individual and combined contributions to the therapeutic potential of cannabis-based treatments, with ongoing research exploring their distinct and interactive effects.

This study aimed to encapsulate cannabigerolic acid (CBGA) in poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles (PEG-PLGA NPs) and investigate the effects of combining CBGA NPs with cannabis-derived terpene-loaded NPs (myrcene [MC], nerolidol [NL], and caryophyllene [CPh]) for potential applications in pain management.

CBGA NPs (152 nm) and terpene-loaded NPs (233-297 nm) were prepared via nanoprecipitation and emulsion-solvent evaporation, respectively, exhibiting a polydispersity index < 0.3 and negative zeta potentials (-23 to -26 mV). Encapsulation efficiency was 98.6 % for CBGA and 13-33 % for terpenes. CBGA release followed a biphasic profile, with ∼ 20 % released within 4 h and sustained release over 72 h. In vitro evaluation used HEK293 cells expressing the nociceptive transient receptor potential vanilloid-1 (TRPV1) channel, a key mediator of pain perception. TRPV1 activation was assessed via calcium influx kinetics (Fluo-4 indicator). The EC50 values were 23.8 µg/mL (CBGA NPs), 8.0 µg/mL (MC NPs), 6.7 µg/mL (NL NPs), and 13.3 µg/mL (CPh NPs). Combinatorial treatments of CBGA NPs with terpene NPs at their respective EC50 concentrations revealed significantly enhanced calcium influx compared to individual NPs, with the strongest interaction observed for CBGA/NL and moderate effects for CBGA/MC. Fluorescence imaging further corroborated these findings.

These results suggest that combining CBGA NPs with terpene-loaded NPs could potentiate pain-relief efficacy, offering a promising strategy for advanced therapeutic formulations.”

https://pubmed.ncbi.nlm.nih.gov/40419035/

“Cannabis sativa has long been valued for its diverse medicinal properties.”

https://www.sciencedirect.com/science/article/pii/S0378517325006039?via%3Dihub

Full spectrum cannabis oil combined with omega-3 fish oil for neuropathic pain management: a novel therapeutic approach

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“Objectives: Current pharmacological treatments for neuropathic pain have limited efficacy and may cause undesirable side effects. Cannabidiol (CBD)-enriched cannabis oil and omega-3 fatty acids (ω-3) have emerged as potential therapeutic options due to their analgesic and anti-inflammatory properties. This study aimed to assess the antinociceptive effects of combining CBD-enriched cannabis oil and ω-3 in rat models of acute and neuropathic pain.

Methods: Using the hot plate test for acute pain and the chronic constriction injury (CCI) model for neuropathic pain, thermal and mechanical hypersensitivity were evaluated. Additionally, walking track analysis and the rotarod test assessed functional recovery of the sciatic nerve. Beyond that, the histological analysis of sciatic nerves exposed the neuropathological findings of the treatments.

Key findings: The combined treatment of CBD-enriched cannabis oil and ω-3 effectively prevented thermal and mechanical hypersensitivity, while also improving motor impairment-induced peripheral neuropathy. Finally, combination treatment showed a protective effect against degeneration resulting from CCI.

Conclusions: These findings underscore the potential of CBD-enriched cannabis oil and ω-3 as a novel therapeutic approach for neuropathic pain management, offering promising implications for future research and clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/40414709/

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgaf027/8148741?redirectedFrom=fulltext&login=false