Category Archives: Pain

Efficacy and mechanism of the antinociceptive effects of cannabidiol on acute orofacial nociception induced by Complete Freund’s Adjuvant in male Mus musculus mice

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Archives of Oral Biology

“Objectives: The objectives were to investigate the efficacy and mechanisms of cannabidiol on orofacial nociception induced by Complete Freund’s Adjuvant (CFA) in male Mus musculus mice.

Design: For the study of efficacy, mice were divided into seven groups: sham; inflammation; and cannabidiol 0.5, 1, 3, 5, and 10 mg. For the study of mechanisms of cannabidiol, mice were divided into six groups: sham, inflammation, calcitonin gene-related peptide (CGRP) antagonist with and without cannabidiol, and vanilloid receptor 1 antagonist with and without cannabidiol. Spontaneous pain-like behaviors, trigeminal nociception, and trigeminal modulating activity were investigated.

Results: CFA injected in the right masseter muscle significantly induced spontaneous pain-like behaviors and the trigeminal nociceptive pathway. This effect was inhibited by injection of 1, 3, 5, and 10 mg of cannabidiol. The 50 % inhibitory concentration of cannabidiol on antinociception was found to be 3 mg/kg. In addition, there was no difference in spontaneous pain-like behaviors with vanilloid receptor 1 antagonist injected before treatment with cannabidiol compared to saline control. Reduced c-fos expression was observed in the trigeminal nucleus caudalis and periaqueductal gray in the group injected with CGRP antagonist before treatment with cannabidiol.

Conclusion: The antinociceptive effects of cannabidiol induced by acute orofacial nociception is mediated by vanilloid receptor 1 but not by CGRP. Cannabidiol can act with peripheral nonpeptidergic neurons and can be used as an alternative drug or as a synergistic medication in pain treatment.”

https://pubmed.ncbi.nlm.nih.gov/36265395/

“Our results may imply that cannabidiol can be used as an alternative drug or as synergistic medication in orofacial pain treatment.”

https://www.sciencedirect.com/science/article/abs/pii/S0003996922002278?via%3Dihub

Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain

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Lopiccolo & Chang in PLoS ONE – BU Linguistics

“This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.”

https://pubmed.ncbi.nlm.nih.gov/36240167/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270543

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

Medical Cannabis Patients Report Improvements in Health Functioning and Reductions in Opiate Use

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“Purpose: Opioid use rates have dropped as North American patients gain access to medical cannabis, indicating a harm reduction role, yet health outcomes remain mostly unexplored. This study presents self-reported medical cannabis use, perceptions of health functioning, and changes in opioid pain medication use in Florida medical cannabis patients.

Methods: Patients (n = 2,183) recruited from medical dispensaries across Florida completed a 66-item cross-sectional survey that included demographic, health, and medication usage items, along with items from the Medical Outcomes Survey (SF-36) to assess health functioning before and after cannabis initiation.

Results: Most participants were between the ages of 20 and 70 years of age (95%), over 54% were female, 47% were employed, and most (85%) were white. Commonly reported ailment groups were Pain and Mental Health combined (47.92%), Mental Health (28.86%) or Pain (9.07%). Health domains of bodily pain, physical functioning, and social functioning improved while limitations due to physical and emotional problems were unchanged. Most patients rated medical cannabis as being important to their quality of life. Many (60.98%) reported using pain medications prior to medical cannabis, 93.36% of these reported a change in pain medication after medical cannabis. The majority of participants (79%) reported either cessation or reduction in pain medication use following initiation of medical cannabis and 11.47% described improved functioning.

Conclusions: The findings suggest that some medical cannabis patients decreased opioid use without harming quality of life or health functioning, soon after the legalization of medical cannabis. The public health implications of medical cannabis as an alternative pain medication are discussed.”

https://pubmed.ncbi.nlm.nih.gov/36168127/

“In conclusion, some patients may reduce or even cease use of OBPM upon access to medical cannabis, potentially without harming quality of life or health functioning. This is suggestive of the harm reduction role and opioid-sparing effects of medical cannabis in a quality-controlled and regulated medical-use only state. Given the great individual and societal costs associated with the opioid crisis (Florence et al., 2021; National Institute on Drug Abuse, n.d.), the public health implications of these findings are important to consider.”

https://www.tandfonline.com/doi/full/10.1080/10826084.2022.2107673

Self-Reported Cannabis Use Is Associated With a Lower Rate of Persistent Opioid Use After Total Joint Arthroplasty

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Arthroplasty Today (@ArthroToday) / Twitter

“Background: Legalization of cannabis, along with concern over prescription opiate use, has garnered interest in cannabis for adjuvant pain control. This study examines the relationship between cannabis and opioid consumption after total hip (THA) or knee (TKA) arthroplasty.

Methods: Patients undergoing primary THA or TKA with minimum 6-month follow-up who self-reported cannabis use were retrospectively reviewed. A total of 210 patients (128 TKAs and 82 THAs) were matched by age; gender; type of arthroplasty; Charlson Comorbidity Index; and use of nicotine, antidepressants, or benzodiazepines to patients who did not self-report cannabis use. Patients receiving an opioid prescription after 90 days postoperatively were classified as persistent opioid users (POUs). Duration of opioid use (DOU) was calculated for non-POU patients as the time between surgery and their last opioid prescription. Differences in inpatient morphine milligram equivalents (MMEs), outpatient MMEs, POU, and DOU were analyzed.

Results: Cannabis users required equivalent inpatient and outpatient MMEs. There was no difference in DOU. There was a significant difference in POU between cannabis users and matched controls (1.4% [n = 3] vs 9.5% [n = 20], P < .001, respectively). Grouping patients by TKA or THA, there remained a difference in POU for TKA (1.5% [n = 2] vs 10.9% [n = 14], P = .002) and THA (1.2% [n = 1] vs 7.3% [n = 6], P = .04). There was no difference in inpatient or outpatient MMEs or DOU for THA and TKA patients.

Conclusions: There is a reduced rate of POU in patients who self-report perioperative cannabis use. Prospective studies are needed to clarify the role of cannabis as an adjunct to perioperative pain control.”

https://pubmed.ncbi.nlm.nih.gov/36158462/

“This study helps to shed light on what role if any cannabis should play as a part of an opioid-sparing multimodal pain protocol after TJA. Self-reported perioperative cannabis use appeared to significantly reduce the number of patients that persistently used opioids greater than 90 days after TJA from 9.5% to 1.4%.”

https://www.arthroplastytoday.org/article/S2352-3441(22)00164-9/fulltext

Preoperative cannabis use does not increase opioid utilization following primary total hip arthroplasty in a propensity matched analysis

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SpringerLink

“Purpose: The recreational and medical use of cannabis is being legalized worldwide. Its use has been linked to an increased risk of developing opioid use disorders. As opioids continue to be prescribed after total hip arthroplasty (THA), the influence that preoperative cannabis use may have on postoperative opioid consumption remains unknown. The purpose of this study was to assess the relationship between preoperative cannabis use and opioid utilization following primary THA.

Methods: We identified all patients over the age of 18 who underwent unilateral, primary THA for a diagnosis of osteoarthritis at a single institution from February 2019 to April 2021. Our cohort was grouped into current cannabis users (within 6 months of surgery) and those who reported never using cannabis. One hundred and fifty-six current users were propensity score matched 1:6 with 936 never users based on age, sex, BMI, history of chronic pain, smoking status, history of anxiety/depression, ASA classification and type of anesthesia. Outcomes included inpatient and postdischarge opioid use in morphine milligram equivalents.

Results: Total inpatient opioid utilization, opioids refilled, and total opioids used within 90 postoperative days were similar between the groups.

Conclusion: In propensity score matched analyses, preoperative cannabis use was not independently associated with an increase in inpatient or outpatient, 90-days opioid consumption following elective THA.”

https://pubmed.ncbi.nlm.nih.gov/36129515/

https://link.springer.com/article/10.1007/s00402-022-04619-7

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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pubmed logo

“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/

Practical Considerations for the Use of Cannabis in Cancer Pain Management-What a Medical Oncologist Should Know

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jcm-logo

“Pain is a highly debilitating emotional and sensory experience that significantly affects quality of life (QoL). Numerous chronic conditions, including cancer, are associated with chronic pain. In the setting of malignancy, pain can be a consequence of the tumor itself or of life-saving interventions, including surgery, chemotherapy, and radiotherapy. Despite significant pharmacological advances and awareness campaigns, pain remains undertreated in one-third of patients. To date, opioids have been the mainstay of cancer pain management. The problematic side effects and unsatisfactory pain relief of opioids have revived patients’ and physicians’ interest in finding new solutions, including cannabis and cannabinoids. The medical use of cannabis has been prohibited for decades, and it remains in Schedule 1 of the Misuse of Drugs Regulations. Currently, the legal context for its usage has become more permissive. Various preclinical and observational studies have aimed to prove that cannabinoids could be effective in cancer pain management. However, their clinical utility must be further supported by high-quality clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36078963/

https://www.mdpi.com/2077-0383/11/17/5036/htm

Long-term effects of a diet supplement containing Cannabis sativa oil and Boswellia serrata in dogs with osteoarthritis following physiotherapy treatments: a randomised, placebo-controlled and double-blind clinical trial

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“Dogs are commonly affected by Osteoarthritis (OA). Different approaches can be used to alleviate animals’ symptoms. In this randomised, placebo-controlled and double-blind clinical trial, we performed a three months follow-up study assessing the efficacy of a food supplement containing natural ingredients (Cannabis sativa oil, Boswellia serrata Roxb. Phytosome® and Zingiber officinale extract) in dogs with OA after the interruption of physiotherapy that was performed during the previous three months. Inflammation and oxidative stress were reduced in the treated group (higher glutathione (GSH) and lower C-reactive protein [CRP] levels in blood) as well as chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/36067506/

https://www.tandfonline.com/doi/abs/10.1080/14786419.2022.2119967?journalCode=gnpl20