Category Archives: Chronic Pain

Medicinal Cannabis for the Treatment of Chronic Refractory Pain: An Investigation of the Adverse Event Profile and Health-Related Quality of Life Impact of an Oral Formulation

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Karger Publishers Further Expands into Open Access and Open Science | STM Publishing News

“Introduction: Medicinal cannabis is prescribed in Australia for patients with chronic refractory pain conditions. However, measures of safety and effectiveness of different cannabinoids are lacking. We designed an observational study to capture effectiveness, adverse events (AEs), and health-related quality of life (HRQoL) measures in patients prescribed an oral medicinal cannabis formulation at Cannabis Access Clinics through the Cannabis Access Clinics Observational study (CACOS).

Objectives: We aimed to evaluate effectiveness, reported AEs, and change in patient-reported outcomes in individuals prescribed a cannabinoid oil formulation for management of chronic pain.

Methods: A cross-sectional analysis was conducted on patients prescribed an oil formulation of Δ9-tetrahydrocannabinol and cannabidiol for pain symptoms of at least 3-month duration. Clinician-reported AEs were organized by system, organ, class, and frequency. Analysis of patient-reported responses to a questionnaire was conducted using published minimal clinically important differences to determine meaningful change in HRQoL over time.

Results: More than half (n = 91/151, 60.3%) of the participants experienced at least one AE during the observation period (mean 133 ± 116 days). No serious AEs were reported. Patient-reported pain impact scores were significantly reduced across the cohort (p = 0.034), and pain intensity scores verged on significance (p = 0.053). The majority of patients saw meaningful improvements in sleep (49.3%) and fatigue (35.6%).

Conclusion: This analysis presents real-world data collected as part of standard of care. More than one-third of patients benefited from oral medicinal cannabis, which is impactful given the refractory nature of their pain. Amelioration of the impact of pain confirms continued prescribing of this formulation and validates our observational methodology as a tool to determine the therapeutic potency of medicinal cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/35950052/

“This is a clinically relevant finding considering that this patient cohort comprises refractory cases where relief has not been obtained with existing medications, including opioids, NSAIDs, and steroids.”

https://www.karger.com/Article/FullText/521492

Medical Cannabis Used as an Alternative Treatment for Chronic Pain Demonstrates Reduction in Chronic Opioid Use – A Prospective Study

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Pain Physician:::::

“Background: Chronic opioid therapy (COT) has been used to treat many chronic pain conditions even with poor evidence for its long-term effectiveness. Medical cannabis has emerged with certain pain-relieving properties, which has led to questions as to its’ potential application, especially in relation to its effect on opioid use.

Objectives: This study investigates a proposed clinical context in offering medical cannabis as a treatment for chronic pain for those already using chronic opioid therapy. It then details patients’ daily morphine milligram equivalent (MME) usage.

Study design: This single-center prospective study follows a group of patients trialing medical cannabis treatment for chronic pain that is already using COT in order to determine individual efficacy. Continued medical cannabis treatment was a decision made by the patient, after trialing medical cannabis, to either continue medical cannabis along with COT at a reduced daily MME, or to revert back to their previous COT regimen.

Setting: This study was performed at the Allegheny Health Network Institute for Pain Medicine in Pittsburgh, Pennsylvania. The state of Pennsylvania legalized medical cannabis in April of 2016, and it became available to patients in February of 2018 through medical dispensaries.

Methods: One hundred and fifteen patients met the inclusion criteria, with the majority of those excluded due to not being treated with COT. Of the 115 who chose to undergo a medical cannabis trial in addition to their COT, 75 chose to remain certified for medical cannabis as they had significant pain relief and subsequently weaned down on opioids. Additionally, of the 115 choosing to undergo a medical cannabis trial, 30 chose to be decertified due to ineffectiveness or side effects, and those were placed back on their COT regimen. The other 10 were not included for other denoted reasons. Compliance was monitored through urine drug screens (UDS).

Results: There was a 67.1% average decrease in daily MME/patient from 49.9 to 16.4 MME at the first follow-up. There was a 73.3% decrease in MME at second follow-up from 49.9 to 13.3 MME with an ANOVA analysis denoting a significant difference of P < 0.0001.

Limitations: The period of follow-up presented at this point includes their first 6 months of treatment with medical cannabis and COT concomitantly.

Conclusions: Presenting medical cannabis to chronic pain patients on COT should be done in the context of a patient choice between medical cannabis WITH decrement of COT or continued current dose of COT in order to maximize effectiveness in opioid reduction as well as to limit polypharmacy concerns regarding medical cannabis. Allowing for a temporary short-term period where patients may trial medical cannabis, while concomitantly gradually weaning their COT, is also essential in determining medical cannabis’ individual effectiveness for that patient’s specific type of chronic pain, which should serve to maximize long-term opioid reduction results and hence decrease opioid-related overdose deaths.”

https://pubmed.ncbi.nlm.nih.gov/35051158/

https://www.painphysicianjournal.com/linkout?issn=&vol=25&page=E113

Drug-Drug Interaction Between Orally Administered Hydrocodone-Acetaminophen and Inhalation of Cannabis Smoke: A Case Report

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SAGE Journals

“Objective: To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products.

Case summary: A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day pilot protocol. The participant attended two 7-hour in-lab days where he received 10 blood draws each day and completed self-administered pain and anxiety surveys. For both days, the participant took his prescribed dose of hydrocodone/acetaminophen (1/2 tablet of 7.5 mg/325 mg combination product) with the addition of 1 smoked pre-rolled marijuana cigarette (labeled as 0.5 g; 22.17% Δ9-tetrahydrocannabinol; 0.12% cannabidiol) on Day 2. Blood specimens were analyzed using mass spectrometry to quantify the difference of plasma hydrocodone levels between Day 1 and Day 2.

Results: Compared to Day 1, lower levels of pain and anxiety were reported during Day 2 with the addition of cannabis to oral hydrocodone/acetaminophen. Day 2 pharmacokinetic analysis also revealed more rapid absorption and overall lower levels of hydrocodone in plasma.

Discussion: Lower hydrocodone plasma levels in Day 2 may indicate cannabis’s effect on metabolism and reduce the risk of opioid toxicity. The quicker absorption rate of hydrocodone could explain lower pain and anxiety scores reported on the second day.

Conclusion and relevance: A 2-day protocol was able to capture differences across time in pharmacokinetic and pharmacodynamic measurements. Larger studies can be designed to better characterize the potential drug-drug interaction of cannabis and opioids.”

https://pubmed.ncbi.nlm.nih.gov/35898257/

https://journals.sagepub.com/doi/10.1177/00185787211061374

Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat

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“Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain.

The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats.

First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively.

The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role.

In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.”

https://pubmed.ncbi.nlm.nih.gov/35893735/

https://www.mdpi.com/1424-8247/15/8/910

Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis

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ijms-logo

“Cannabis-based terpenes are believed to modulate physiological responses to disease and alter the efficacy of cannabinoids in the so-called “entourage effect”. The monoterpene myrcene can reduce nociception produced by noxious thermal and mechanical stimuli as well as reducing acute inflammation.

The current study examined the role of myrcene and cannabidiol (CBD) in controlling chronic joint inflammation and pain.

Chronic arthritis was induced in male Wistar rats by intra-articular injection of Freund’s complete adjuvant into the right knee. On days 7 and 21 after arthritis induction, joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle contrast analysis) and joint histopathology were assessed.

Local application of myrcene (1 and 5 mg/kg s.c.) reduced joint pain and inflammation via a cannabinoid receptor mechanism. The combination of myrcene and CBD (200 μg) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine production.

These data suggest that topical myrcene has the potential to reduce chronic arthritis pain and inflammation; however, it has no synergistic effect with CBD.”

https://pubmed.ncbi.nlm.nih.gov/35887239/

“In summary, myrcene was found to have anti-inflammatory and analgesic effects in inflammatory joint disease by activating articular cannabinoid receptors. Together, these findings may explain why arthritis patients prefer Cannabis strains rich in myrcene to help manage their pain and inflammation.”

https://www.mdpi.com/1422-0067/23/14/7891/htm

Acidic cannabinoids suppress pro-inflammatory cytokine release by blocking Store-Operated Calcium Entry

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Graphical Abstract

“Cannabis sativa has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remain ill-defined.

In this study we provide the first comprehensive overview of the effects of whole-plant Cannabis extracts and various pure cannabinoids on store-operated calcium (Ca2+) entry (SOCE) in several different immune cell lines.

SOCE is one of the most significant Ca2+ influx mechanism in immune cells and it is critical for the activation of T lymphocytes, leading to the release of pro-inflammatory cytokines and mediating inflammation and T cell proliferation, key mechanisms for maintaining chronic pain.

While the two major cannabinoids cannabidiol (CBD) and trans-Δ9-tetrahydrocannabinol (THC) were largely ineffective in inhibiting SOCE, we report for the first time that several minor cannabinoids, mainly the carboxylic acid derivatives and particularly the cannabigerolic acid (CBGA), demonstrated high potency against SOCE by blocking Calcium Release-Activated Calcium (CRAC) currents. Moreover, we show that this inhibition of SOCE resulted in a decrease of Nuclear Factor of Activated T-cells (NFAT) activation and Interleukin 2 (IL-2) production in human T lymphocytes.

Taken together, these results indicate that cannabinoid-mediated inhibition of a pro-inflammatory target such as SOCE may at least partially explain the anti-inflammatory and analgesic effects of Cannabis.”

https://pubmed.ncbi.nlm.nih.gov/35910331/

https://academic.oup.com/function/advance-article/doi/10.1093/function/zqac033/6634246

“Marijuana plant might hold key to treating chronic inflammation”

https://medicalxpress.com/news/2022-07-marijuana-key-chronic-inflammation.html

Efficacy, Safety, and Regulation of Cannabidiol on Chronic Pain: A Systematic Review

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Archive of "Cureus". - PMC

“We conducted a systematic review to determine the efficacy and safety of cannabidiol (CBD) for chronic pain.

CBD and tetrahydrocannabinol (THC), both from Cannabis plants with almost identical chemical structures, attach to the CB receptor, eliciting different effects like the psychoactivity seen on THC but less or none in CBD.

Regulations of CBD worldwide differ from each other due to the insufficiency of solid evidence to establish its benefit versus the risks. However, a few studies are showing the benefits of CBD not only for chronic pain but also for sleep improvement and quality of life.

In conclusion, CBD is an excellent alternative to an opioid in chronic pain because CBD is non-intoxicating in its pure form. More clinical trials should be done to prove CBD’s significance clinically and statistically.”

https://pubmed.ncbi.nlm.nih.gov/35860716/

“It is essential to know that pure CBD extract is a strong candidate as an alternative to opioid medication since it is nonintoxicating and dependence is less. This systematic review can benefit other researchers and even ordinary people eager to know the latest updates on CBD research on chronic pain. In the future, clinical trials should focus more on using pure CBD extract to treat chronic pain to attain evidence to properly recommend CBD in the health insurance sector so that patients may benefit to the full extent.”

https://www.cureus.com/articles/101310-efficacy-safety-and-regulation-of-cannabidiol-on-chronic-pain-a-systematic-review


Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions

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SpringerLink

“Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells.

The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain.

THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.”

https://pubmed.ncbi.nlm.nih.gov/35796920/

“Tetrahydrocannabinol (THC) and cannabidiol (CBD) combination medicines and CBD-only medicines are prospective new treatments for chronic pain, stress, anxiety, depression, and insomnia, which are all medical conditions in need of better therapeutics. Both THC/CBD combination and CBD-only medicines could provide effective new treatment options for pain and mental health, respectively, and both have good safety and tolerability profiles relative to the current treatments.

THC and CBD combination medicines have a good safety and tolerability profile that is appropriate for opioid stage (stage 2–3) treatment of chronic pain. Low-dose CBD could be used as an initial treatment for chronic pain and for stress, anxiety, depression, and insomnia. High quality efficacy evidence is best for THC/CBD combination medicines for chronic pain and CBD-only medicines for stress and anxiety. “

https://link.springer.com/article/10.1007/s10787-022-01020-z

Patient Experience and Perspective on Medical Cannabis as an Alternative for Musculoskeletal Pain Management

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JAAOS - Journal of the American Academy of Orthopaedic Surgeons

“Introduction: The current rate of opioid prescription is disquieting because of their high abuse potential, adverse effects, and thousands of overdose deaths. This situation imposes urgency in seeking alternatives for adequate pain management. From this perspective, this study aimed to evaluate the experience and the perceived analgesic efficacy of medical cannabis in managing the pain associated with musculoskeletal conditions.

Methods: A 28-question survey was distributed to patients at a major medical cannabis center in Puerto Rico for 2 months. Demographics, medical history, cannabis usage, cannabis use perspective, and analgesic efficacy were assessed in the questionnaire.

Results: One hundred eighty-four patients completed our survey. The majority (67%) were males, and the participants’ average age was 38 years. This study showed an average pain reduction score of 4.02 points on the Numeric Rating Scale among all the participants. Those with musculoskeletal conditions reported a notable average pain reduction score of 4.47 points. In addition, 89% of the participants considered medical cannabis to be more effective than narcotics for adequate pain management.

Conclusions: This study demonstrated that the use of medical cannabis among patients with musculoskeletal conditions effectively reduced pain levels based on their Numeric Rating Scale reported scores.”

https://pubmed.ncbi.nlm.nih.gov/35796526/

“This study showed that the use of medical cannabis among patients with musculoskeletal conditions effectively reduced pain levels based on their NRS reported scores. In addition, most patients using medical cannabis considered that this drug represents a better option than narcotics (ie, opioids) for adequate pain management.”

https://journals.lww.com/jaaosglobal/Fulltext/2022/07000/Patient_Experience_and_Perspective_on_Medical.6.aspx

Cannabinoid 1 and mu-opioid receptor agonists synergistically inhibit abdominal pain and lack side effects in mice

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Society for Neuroscience - Publications

“While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence.

We aimed to investigate if cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses.

Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated dorsal root ganglion (DRG) neurons. Blood oxygen saturation, locomotion and defecation were measured to evaluate side effects.

An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2′-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity or DRG neuron excitability.

Combination of sub-analgesic doses of CB1R and µ-opioid receptor (MOR) agonists decreased VMR; importantly, this analgesic effect was preserved after 6 days of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase (nNOS) and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with MOR.

Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects.

SIGNIFICANCE STATEMENTOne of the most cited needs for patients with abdominal pain are safe and effective treatment options. The effectiveness of opioids in the management of abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace opioids or reduce the doses of opioids to suppress abdominal pain is needed. This study in mice demonstrates that cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of sub-analgesic doses of µ-opioid receptor agonist and CB1R agonist markedly reduce abdominal pain without causing the side effects of high dose opioids. Thus, CB1R agonists, alone or in combination with low-dose opioids, may be a novel and safe treatment strategy for abdominal pain.”

https://pubmed.ncbi.nlm.nih.gov/35790401/