Pain and Depression: A Systematic Review.

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“Pain comorbid with depression is frequently encountered in clinical settings and often leads to significant impaired functioning. Given the complexity of comorbidities, it is important to address both pain and depressive symptoms when evaluating treatment options.

Overall, studies suggested that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. These symptoms could lead to poor physical functional outcomes and longer duration of symptoms. An important biochemical basis for pain and depression focuses on serotonergic and norepinephrine systems, which is evident in the pain-ameliorating properties of serotonergic and norepinephrine antidepressants.

Alternative pharmacotherapies such as ketamine and cannabinoids appear to be safe and effective options for improving depressive symptoms and ameliorating pain. In addition, cognitive-behavioral therapy may be a promising tool in the management of chronic pain and depression.

CONCLUSION:

The majority of the literature indicates that patients with pain and depression experience reduced physical, mental, and social functioning as opposed to patients with only depression or only pain. In addition, ketamine, psychotropic, and cognitive-behavioral therapies present promising options for treating both pain and depression.”

https://www.ncbi.nlm.nih.gov/pubmed/30407234

https://insights.ovid.com/crossref?an=00023727-201811000-00005

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Combined THC and CBD to treat pain in epidermolysis bullosa: a report of three cases.

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“Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain-care in EB however are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been increasingly studied for pain conditions of various etiologies and pose as a novel dimension for pain-care in EB. We present three cases of EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol (THC) and cannabidiol (CBD). All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake. ”

https://www.ncbi.nlm.nih.gov/pubmed/30347109

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.17341

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THC and gabapentin interactions in a mouse neuropathic pain model.

Neuropharmacology

“Clinical studies have shown that the major psychoactive ingredient of Cannabis sativa Δ9-tetrahydrocannabinol (THC) has some analgesic efficacy in neuropathic pain states.

However, THC has a significant side effect profile. We examined whether the profile of THC could be improved by co-administering it with the first-line neuropathic pain medication gabapentin.

These findings indicate that gabapentin synergistically enhances the anti-allodynic actions of THC and improves its therapeutic window.

Thus, THC may represent a potential adjuvant for neuropathic pain medications such as gabapentin.”

https://www.ncbi.nlm.nih.gov/pubmed/30312630

https://www.sciencedirect.com/science/article/pii/S0028390818307779?via%3Dihub

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A systematic review on the neuroprotective perspectives of beta-caryophyllene.

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“Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect.

This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords “beta (β)-caryophyllene” and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action.

A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer’s disease.

Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.”

https://www.ncbi.nlm.nih.gov/pubmed/30281175

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Cannabinoid Delivery Systems for Pain and Inflammation Treatment.

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“There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions.

The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety.

The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes.

Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.”

https://www.ncbi.nlm.nih.gov/pubmed/30262735

https://www.mdpi.com/1420-3049/23/10/2478

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Association of Cannabinoid Administration With Experimental Pain in Healthy Adults A Systematic Review and Meta-analysis

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“Patients have reliably endorsed the belief that cannabis is helpful in alleviating pain.

Cannabinoids (the collective term for all of the drugs examined in this study, including plant-based cannabis, which can contain multiple compounds) have long been considered effective for reducing pain and are frequently proposed as treatment options in pain management.

Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes.

Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain.”

“Cannabinoid drugs make pain feel ‘less unpleasant, more tolerable'”  https://www.sciencedaily.com/releases/2018/09/180919111454.htm

“Medical marijuana increases pain threshold for patients”  https://www.upi.com/Health_News/2018/09/19/Medical-marijuana-increases-pain-threshold-for-patients/1771537292969/?rc_fifo=1

“Study reveals cannabinoid drugs make pain feel ‘less unpleasant, more tolerable'”  https://medicalxpress.com/news/2018-09-reveals-cannabinoid-drugs-pain-unpleasant.html

“Cannabinoid drugs reduce perceived unpleasantness of painful stimuli and increase tolerance” https://www.news-medical.net/news/20180919/Cannabinoid-drugs-reduce-perceived-unpleasantness-of-painful-stimuli-and-increase-tolerance.aspx

“Cannabinoids appear to increase pain tolerability”  https://www.healio.com/psychiatry/practice-management/news/online/%7B7626bb3f-ce35-4968-99bc-50ecdaac79b7%7D/cannabinoids-appear-to-increase-pain-tolerability

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Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain.

“Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

OBJECTIVES:

The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA.

RESULTS:

CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.

CONCLUSION:

CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30225659

https://link.springer.com/article/10.1007%2Fs00213-018-5034-1

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Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

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“Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke.

In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion.

These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.”

https://www.ncbi.nlm.nih.gov/pubmed/30223868

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0395-2

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Emerging Evidence for Cannabis’ Role in Opioid Use Disorder.

 Cannabis and Cannabinoid Research cover image “The opioid epidemic has become an immense problem in North America, and despite decades of research on the most effective means to treat opioid use disorder (OUD), overdose deaths are at an all-time high, and relapse remains pervasive.

Although there are a number of FDA-approved opioid replacement therapies and maintenance medications to help ease the severity of opioid withdrawal symptoms and aid in relapse prevention, these medications are not risk free nor are they successful for all patients. Furthermore, there are legal and logistical bottlenecks to obtaining traditional opioid replacement therapies such as methadone or buprenorphine, and the demand for these services far outweighs the supply and access.

To fill the gap between efficacious OUD treatments and the widespread prevalence of misuse, relapse, and overdose, the development of novel, alternative, or adjunct OUD treatment therapies is highly warranted. In this article, we review emerging evidence that suggests that cannabis may play a role in ameliorating the impact of OUD. Herein, we highlight knowledge gaps and discuss cannabis’ potential to prevent opioid misuse (as an analgesic alternative), alleviate opioid withdrawal symptoms, and decrease the likelihood of relapse.

Conclusion: The compelling nature of these data and the relative safety profile of cannabis warrant further exploration of cannabis as an adjunct or alternative treatment for OUD.”

https://www.ncbi.nlm.nih.gov/pubmed/30221197

https://www.liebertpub.com/doi/10.1089/can.2018.0022

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Restored Self: A Phenomenological Study of Pain Relief by Cannabis.

Pain Medicine

“OBJECTIVE:

To explore the subjective experience of pain relief by cannabis.

RESULTS:

Three key themes that emerged from the analysis were explored: 1) the Sigh of Relief, describing the corporal sensation of using cannabis, including a sense of relaxation and reduction in pain; 2) the Return to Normality, describing the comprehensive effect of using cannabis, including an increased ability to sleep, focus, and function; and 3) the Side Effects of using cannabis.

CONCLUSIONS:

We propose the term Restored Self to conceptualize the effect of medical cannabis. Restored Self is the experience of regaining one’s sense of self, sense of normality, and sense of control over one’s life.”

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