Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study

pubmed logo

“The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.”

An answered call for aid? Cannabinoid clinical framework for the opioid epidemic

pubmed logo

“Background: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools.

Main body: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids.

Conclusion: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.”

“Resistance to cannabis-based medicines for the opioid epidemic may have many origins, particularly the stigma associated with recreational cannabis use. That said, the evidence to date suggests that it is time for a sea change in the clinical approach to cannabis for pain management and OUD. Throughout the history of science and clinical medicine, there have been transformative changes that were initially considered heretical: hand hygiene as a means to prevent infection prior to germ theory, therapy for H. pylori to combat peptic ulcer disease, and even the genetic basis of cancer were all dismissed by their era’s established medical communities. Similarly, we face great resistance to the implementation of CBD and other cannabinoids for treatment-resistant chronic illnesses, despite the compelling evidence, strong overall safety profile, and urgent need. Many of our patients have already begun their own self-guided journey into pain management with cannabinoids and the burden is now on providers to consolidate the information available, conduct more rigorous research, form best practices, and implement guidelines that will inform both the field and those we care for without stigma.”

Cannabis Versus Opioids for Pain

pubmed logo

“In the human body, pain is an inherent alarm system that activates when there is actual or potential damage, directing an individual’s attention toward the issue. Pain is a frequently cited reason for seeking healthcare or medical assistance. Pain encompasses various elements, including nociception, the perception of pain, suffering, and pain behaviors. Although pain is a fundamental mechanism, it can become burdensome when it persists for an extended period, leading to suffering and pain-related behaviors. Chronic and unrelenting pain can cause psychological, physical, and emotional distress, adding further strain to individuals.

The search for an ideal pain relief medication has been an ongoing endeavor since ancient times, as certain types of pain still lack definitive treatment options. Several strategies have been developed to address intractable pain that does not respond to nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids being the mainstay in many pain management protocols. In recent years, there has been growing and promising evidence suggesting the potential effectiveness of cannabinoids in the management of chronic pain.”

Can cannabidiol have an analgesic effect?

pubmed logo

“Background: Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.

Objectives and methods: We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.

Results and conclusion: The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD’s analgesic effect are currently being extensively studied.”

Dramatic efficacy of cannabidiol on refractory chronic pain in an adolescent with sickle cell disease

pubmed logo

“Here, we report a dramatic efficacy of cannabidiol in an adolescent with SCD suffering from chronic pain refractory to other analgesics, with complete regression of chronic pain and rapid plasma histamine level normalization after treatment.”

“In conclusion, we report here for the first time a case of refractory chronic pain with dramatic improvement after CBD treatment in an adolescent with SCD. The CBD oral solution Epidiolex has been approved by the US Food and Drug Administration since June 2018 and by the European Medicine Agency since January 2023 for management of refractory epilepsy. As it seems to be a well-tolerated drug, CBD could represent a promising therapeutic perspective for patients with SCD suffering from chronic pain.”

Cannabis use to manage opioid cravings among people who use unregulated opioids during a drug toxicity crisis

pubmed logo

“Background: Accumulating evidence has indicated that cannabis substitution is often used as a harm reduction strategy among people who use unregulated opioids (PWUO) and people living with chronic pain. We sought to investigate the association between cannabis use to manage opioid cravings and self-reported changes in opioid use among structurally marginalized PWUO.

Methods: The data were collected from a cross-sectional questionnaire administered to PWUO in Vancouver, Canada. Binary logistic regression was used to analyze the association between cannabis use to manage opioid cravings and self-reported changes in unregulated opioid use.

Results: A total of 205 people who use cannabis and opioids were enrolled in the present study from December 2019 to November 2021. Cannabis use to manage opioid cravings was reported by 118 (57.6%) participants. In the multivariable analysis, cannabis use to manage opioid cravings (adjusted Odds Ratio [aOR] = 2.13, 95% confidence interval [CI]: 1.07, 4.27) was significantly associated with self-reported reductions in opioid use. In the sub-analyses of pain, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among people living with moderate to severe pain (aOR = 4.44, 95% CI: 1.52, 12.97). In the sub-analyses of males and females, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among females (aOR = 8.19, 95% CI: 1.20, 55.81).

Conclusions: These findings indicate that cannabis use to manage opioid cravings is a prevalent motivation for cannabis use among PWUO and is associated with self-assessed reductions in opioid use during periods of cannabis use. Increasing the accessibility of cannabis products for therapeutic use may be a useful supplementary strategy to mitigate exposure to unregulated opioids and associated harm during the ongoing drug toxicity crisis.”

Offering an Alternative to Persons with Chronic Pain: How Access to Cannabis May Provide an Off-Ramp from Undesired Prescription Opioid Use

pubmed logo

“Background: Chronic pain (CP) is experienced by as many as 50 million Americans and can negatively impact physical and mental health. Prescribing opioids is the most common approach to address moderate to severe CP though these potent analgesics are associated with a significant number of side effects. One alternative some Americans are turning to for CP management is cannabis. In addition to serving as an alternative, many individuals with CP use cannabis in addition to using prescription opioids. This study examined individuals with CP who enrolled in the state of Illinois’ opioid diversion program, the Opioid Alternative Pilot Program (OAPP), which offers individuals aged 21 and older a separate pathway to access medical cannabis if they have or could receive a prescription for opioids as certified by a licensed physician.

Methods: Cross-sectional survey data were collected from 450 participants. We described participants and compared those who use only cannabis with those who use cannabis and opioids.

Results: While 16% of the respondents were cannabis-only users, 84% of the respondents were co-users of opioids and cannabis. Both groups considered opioid use risky (100% cannabis-only, 89% co-users,). The majority (73%) of respondents sought to completely stop or never start using opioids for CP. Cannabis-only users reported lower levels of pain compared to co-users. Co-users (85%) were more likely to have their routine provider as a cannabis certifying physician than cannabis-only users (69%).

Conclusion: With increasing clinical evidence, legalization and acceptance, researchers should continue to examine how cannabis may be a viable alternative to reduce the risk of prescription opioid side effects, misuse, or dependence. Our findings also inform health care providers and state policymakers who increasingly are being asked to consider how cannabis may reduce the potential for harmful outcomes among persons with CP who use prescription opioids.”

Perceived Effectiveness of Medical Cannabis Among Adults with Chronic Pain: Findings from Interview Data in a Three-Month Pilot Study

pubmed logo

“Objectives: Patient-reported outcomes are critical to evaluate the effectiveness of medical cannabis as an alternative treatment for chronic pain. This study examined the perceived effectiveness of medical cannabis for chronic pain management among middle-aged and older adults newly initiating medical cannabis.

Methods: Interview data from participants in a three-month pilot study were analyzed to assess the perceived effectiveness of medical cannabis on chronic pain and related outcomes. The interview was conducted after approximately one month of usage and responses were analyzed using the RADaR (Rigorous and Accelerated Data Reduction) technique.

Results: 51 adults initiating medical cannabis for chronic pain were interviewed (24 women, 27 men, mean age 54.4, SD = 12.0), with the majority (n=41) identifying as Non-Hispanic White followed by Non-Hispanic Black (n=7), Multi-racial (2), Hispanic White (1). Most study participants (62.7%) reported MC being overall effective. Common benefits included reduced pain intensity, anxiety, and dependency on pain and psychiatric medications. Improvements in physical functioning, sleep quality, and mood were reported. Common challenges included difficulty finding a suitable product or dose, experiencing side effects such as ‘undesired high’, ‘stomach issues’, and a limited ‘threshold of pain’ treatable by the product.

Discussion: Findings suggest most participants perceived medical cannabis to be overall effective for chronic pain management. Participants reported improved physical and mental functioning and reduced use of pain and psychiatric medications. Future research systematically assessing side effects, dosage and mode of consumption is needed to further evaluate the outcomes among adults initiating medical cannabis.”

Tolerability and Efficacy of a 10:25 Preparation of Δ9-Tetrahydrocannabinol and Cannabidiol for Treatment of Chronic Back or Neck Pain: A Multiple-Dose Escalation Study

pubmed logo

“Introduction: The aim was to demonstrate the safety and tolerability of cannabidiol (CBD) with Δ9-THC in patients with moderate to severe chronic back or neck pain unresponsive to over-the-counter non-opioid analgesics.

Methods: This was a non-randomized, single-arm, open-label study. Participants received escalating doses of an oromucosal-administered combination containing 10 mg/mL of Δ9-THC, 25 mg/mL of CBD. On day 1, patients received once-daily 0.5 mL Cybis® 10:25 (5 mg Δ9-THC plus 12.5 mg CBD daily), escalated at days 8, 15, and 22 to 0.5 mL twice-daily (bd) (10 mg Δ9-THC plus 25 mg CBD daily), 1.0 mL bd (20 mg Δ9-THC plus 50 mg CBD daily), and 1.5 mL bd (30 mg Δ9-THC plus 75 mg CBD daily), respectively. The primary outcome was safety and tolerability, with secondary objectives including pharmacokinetic and efficacy outcomes.

Results: 28 patients were enrolled in the study. Their median age was 63.3 years, and half were female. The median history of neck/back pain was 10 years. The pharmacokinetics following single doses of 0.5 mL were variable; however, there were dose-dependent increases in trough levels of CBD and Δ9-THC. Cybis® 10:25 was well tolerated, with the majority of adverse events of mild severity. The most common adverse events were nausea, vomiting, fatigue, dizziness, headache, paresthesia, and anxiety. There were dose-dependent improvements in numerical pain rating scores (p < 0.001), with clinically significant reductions in pain at 1.0 mL bd and 1.5 mL bd doses (28.8% and 34.1% reductions, respectively, p < 0.001). Depressive symptoms and stress had dose-dependent reductions (p = 0.0182, p < 0.01, respectively).

Conclusion: In patients with chronic neck/back pain, CBD and Δ9-THC are well tolerated and doses of 1.0 mL bd and 1.5 mL bd showed clinically significant reductions in pain compared to baseline pain scores.”

Anti-allodynic and medullary modulatory effects of a single dose of delta-9-tetrahydrocannabinol (THC) in neuropathic rats tolerant to morphine

pubmed logo

“Neuropathic pain (NP) is often treated with opioids, the prolonged use of which causes tolerance to their analgesic effect and can potentially cause death by overdose. The phytocannabinoid delta-9-tetrahydrocannabinol (THC) may be an effective alternative analgesic to treat NP in morphine-tolerant subjects. Male Wistar rats developed NP after spared nerve injury, and were then treated with increasing doses of THC (1, 1.5, 2, 2.5, and 5 mg/kg, intraperitoneally) which reduced mechanical allodynia at the dose of 2.5 and 5 mg/kg. Another group of NP rats were treated with morphine (5 mg/kg, twice daily for 7 days, subcutaneously), until tolerance developed, and on day 8 received a single dose of THC (2.5 mg/kg), which significantly reduced mechanical allodynia. To evaluate the modulation of THC in the descending pain pathway, in vivo electrophysiological recordings of pronociceptive ON cells and antinociceptive OFF cells in the rostroventral medulla (RVM) were recorded after intra-PAG microinjection of THC (10 μg/μl). NP rats with morphine tolerance, compared to the control one, showed a tonic reduction of the spontaneous firing rate of ON cells by 44%, but the THC was able to further decrease it (a hallmark of many analgesic drugs acting at supraspinal level). On the other hand, the firing rate, of the antinociceptive OFF cells was increased after morphine tolerance by 133%, but the THC failed to further activate it. Altogether, these findings indicate that a single dose of THC produces antiallodynic effect in individuals with NP who are tolerant to morphine, acting mostly on the ON cells of the descending pain pathways, but not on OFF cells.”