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ASRA Pain Medicine Update

Clinical Approach to Medical Cannabinoid Use in Chronic Pain: A Problem-Based Learning Discussion

Sep 10, 2023, 18:11 PM by Mark Pressler, MD; Tracy Oyugi, MD; Ibrahim Umer, DO; Brian Brenner, MD

Disclaimer: The intent of this case is to provide an educational exercise for trained medical professionals to better understand the current evidence for the use of medical cannabinoids in chronic pain medicine and their physiologic mechanisms. This case is not intended to recommend for or against the use of cannabis or cannabinoids. This case stem does not reflect the personal views of the authors or ASRA Pain Medicine on the topic of medical cannabinoids in pain medicine. 

 

An 87-year-old male with a past medical history of coronary artery disease complicated by non-ST elevation myocardial infarction (NSTEMI) with subsequent coronary artery bypass surgery performed 15 years ago (left ventricular ejection fraction of 50% with elevated left-sided filling pressures), asymptomatic moderate aortic stenosis complicated by left ventricular hypertrophy, diabetes mellitus type 2 with neuropathy (HbA1c of 6.8%), chronic kidney disease class 3b, former tobacco use (quit after his NSTEMI), and severe bilateral knee osteoarthritis (OA) (status post-right total knee arthroplasty [TKA] 20 years ago) presents to his pain physician for assistance with his chronic knee pain and diabetic neuropathy.

He recently went to his orthopedic surgeon, who stated that his medical comorbidities and age precluded him from left-sided TKA. He is taking hydrocodone 10/325 three times a day and experiencing constipation causing abdominal pain that is waking him from sleep multiple times nightly, significantly impacting his quality of life. His diabetic neuropathy has been getting worse, which worsens sleep disturbance. He notes historical use of diclofenac, which improved his OA pain but worsened kidney function, leading his primary care physician to discontinue it. He received a left-sided knee radiofrequency ablation, which improved his pain for 3 weeks; however, at his follow up appointment, his pain has returned to baseline.

 

Questions

You work in a state in which medical cannabis use is legal, and you recently obtained your license to recommend cannabinoid products. Based on his medical history, which of the following is the best next option to try for his osteoarthritis pain?

A. Nonsteroidal anti-inflammatory drug, such as diclofenac
B. High tetrahydrocannabinol (THC)/low cannabidiol (CBD)
C. Low-dose opioid
D. CBD only

D is the most correct answer. There are many phytocannabinoids and synthetic cannabinoids that are beyond the scope of this review1-3; delta9-THC and CBD are most commonly studied in a medicinal context.1,3-5

THC is a psychoactive compound; evidence supports its use in neuropathic pain. It also has analgesic, anti-inflammatory, antiemetic, and antioxidant properties.1,2,4-8 CBD has anti-inflammatory, analgesic, and anticonvulsant properties.1,2,4-8 CBD has preclinical data supporting its use in arthritic conditions.1 CBD may work synergistically to improve THC’s analgesia and attenuate its psychoactive/cognitive side effects.1,3,9 Data shows that a THC:CBD combination is superior to THC alone or placebo in treating cancer pain.5,8 Nabiximol is a cannabinoid medication formulated with a standardized combination of THC and CBD that is currently being investigated in the treatment of chronic pain and other conditions.10,11

Choice A is less correct because nonsteroidal anti-inflammatory drugs can lead to or worsen kidney injury in both young and old patients, especially those susceptible to chronic kidney disease at baseline.12

Choice B is less correct because starting on a high-THC concentration first can lead to side effects of sedation and dizziness and can worsen cardiac symptoms. If used, the recommendation is to start with a low dose and closely monitor effects.8

Choice C is less correct because opioids are a poor choice for long-term treatment of osteoarthritis and neuropathic pain due to issues with tolerance, hyperalgesia, abuse potential, and side effects like nausea, constipation, and sedation. In addition, this patient is already taking opioids and experiencing moderate negative side effects; therefore, he is unlikely to respond to an additional low-dose opioid.13

 

After he started taking a standardized CBD product, he notes his knee osteoarthritis pain has improved. He is surprised to note that his sleep has improved as well. However, his diabetic neuropathy is worsening. Trials of gabapentin have led to oversedation without improvement in quality of sleep, and this patient’s use of pregabalin has only been moderately effective.

What cannabinoid/cannabinoid combination would be potentially effective for his chronic neuropathic pain?

A. THC only
B. High THC/low CBD
C. Low THC/high CBD
D. CBD only

Choice C is the most correct. In addition to preclinical data showing increased pain tolerance in induced pain studies,5,8 evidence supports the use of THC in multiple neuropathic pain states, such as diabetic peripheral neuropathy, complex regional pain syndrome, peripheral mononeuropathies, and phantom limb pain.5,8-10,14-17
No specific guidelines are available for dosing THC or CBD, and current recommendations focus on starting THC at a low dose to avoid its psychoactive side effects.1,17 A commentary from the University of Michigan described a dosing approach that starts with CBD at 5-10 mg, two times daily, increasing weekly over 1-2 months until the patient notes pain relief.1 Another University of Michigan article cites maximum CBD doses of 40-50 mg daily in divided doses.2 The article recommends that patients not experiencing relief with CBD start THC at 1-2.5 mg nightly and increasing slowly,1,2 with a max of 30-40 mg per day.2

Because the patient in this case experienced arthritic relief with CBD, but not neuropathic relief, adding a low dose of THC is reasonable. Given his age and comorbidities, starting at 1 mg nightly is reasonable. Choice A is less correct because the patient noted relief with CBD. Choice B is less correct because, with his age and cardiac history, adding a large amount of THC may lead to unwanted side effects.

 

You decide to add low-dose THC to the patient’s formulation of recommended CBD, which he tolerates well. He reports his diabetic neuropathy has improved as well as his functional status. He denies dizziness with the low-THC formulation. You discuss adding duloxetine to his regimen as well. He agrees, and his neuropathy improves further. He admits to a ground-level fall with palpitations (without hitting his head) when he tried his friend’s THC gummies. His visit to the emergency room was unremarkable, showing there was no intracerebral event, and his cardiac workup was negative.

You counsel the patient on THC side effects, which include what?

A. Dizziness/sedation
B. Increase in heart rate
C. Issues with memory and attention with long-term use
D. All of the above

Choice D is the most correct. THC has psychoactive effects (euphoria or altered perception)5,7,14 and can induce cognitive impairment (decreased reaction time, decision making, memory, attention).5 Acute cognitive changes are reported to be greatest in patients 1 hour after smoking THC-containing compounds and 1-2 hours after oral intake of THC-containing compounds (although absorption is variable5); these changes were undetectable at 3-4 hours.5 Evidence finds that daily smokers have longer impairment (than once a month users) with decreased performance on tests 19 hours after use and cognitive impairment for up to 7 days after use.5 Literature has not found a clear link between adolescent use (age 16-20) and poorer neuropsychotic performance.8 CBD adverse effects include fatigue, diarrhea, and anorexia.4

Evidence suggests that cannabinoids increase heart rate (average >19 beats/minute), which may be concerning for those with severe/unstable cardiac history.3,5 Carcinogens have been found in marijuana smoke; however, studies looking at a link between marijuana are mixed.5 One study found a link between marijuana and lung cancer; three did not.5 Links established between marijuana and testicular carcinoma or transitional cell carcinoma did not control for tobacco use.5 Ingestion of marijuana by smoking can increase symptoms of chronic bronchitis; however there is no link between marijuana and chronic obstructive pulmonary disease.5

Drug-drug interactions can occur between THC and/or CBD and other medications. THC and CBD can cause competitive inhibition of CYP2C9 and CYP2C19, with CBD being a more potent inhibitor. THC is metabolized by CYP3A4. Medications that induce/inhibit these enzymes can change THC or CBD levels.3 THC and CBD can increase levels of warfarin, direct oral anticoagulants, and clopidogrel.3 Guidelines recommend checking international normalized ratio within 3 days of starting cannabinoids and close monitoring of direct oral anticoagulants.3

 

At a subsequent follow-up appointment, the patient states that he and his primary care doctor want to decrease his opioid prescription now that his pain has improved. Which of the following is correct about chronic opioids and the use of THC/CBD?

A. THC can lead to greater opioid requirements in patients taking long-term opioids.
B. THC can decrease opioid requirements.
C. Opioids with cannabinoids can increase risk of sedation.
D. Long-term opioids are a superior option for treating long-term pain.
E. B and C are correct.

Choice E is the most correct. There is little evidence supporting long-term use of opioids.13,18  There is evidence showing that THC can reduce opioid requirements,5,8,16-19 with patients reporting using cannabis as a substitute for opioids.17,18 In addition, there is evidence supporting improved pain control with the addition of cannabinoids to opioid pain management.5,16-19 One study looking at opioid cessation among patients with chronic pain found a significant negative association between current marijuana use and the likelihood of resuming opioids in the next year.18

One study comparing depression and anxiety scores among patients receiving opioids vs. marijuana found higher rates of depression and anxiety in patients with chronic pain who are treated with opioids vs marijuana. Another longitudinal study followed patients after they weaned from opioids (as compared to before); 53% of patients noted similar or improved sleep, 61% reported improved or similar ability to perform day-to-day activities, 65% reported better or same quality of life, 63% reported better or same level of anxiety, and 74% reported better or same mood.18

 

What other pain states have evidence of benefit from THC and/or CBD?

A. Multiple sclerosis (MS)
B. HIV-induced peripheral neuropathy
C. Chronic cancer pain
D. Fibromyalgia
E. All of the above

Choice E is the most correct. In regard to MS, literature supports the treatment of neuropathic pain that develops from MS with both THC and CBD.5,6,8,17 In addition to pain, patients with MS reported improvements in sleep and perceived muscle spasms.6,8 Patients with HIV-associated neuropathy experienced improved pain control with marijuana compared with placebo.5,8,17 In addition, dronabinol is indicated for HIV-induced nausea and vomiting.14

Opioids are commonly used in the treatment of cancer pain, and evidence suggests cannabinoids are a possible adjunct.5-8,19-21 One trial placed patients with opioid-resistant cancer pain in a THC:CBD combination (1:1 ratio) group, THC alone group, and placebo group. The THC:CBD group had superior pain control compared with placebo; however the THC alone group did not.22 A systematic review found marijuana led to an improvement in pain relief, physical functioning, and sleep quality in those with cancer pain.21 One study reviewed a cross section of cancer survivors, finding a 5%-20% relative reduction in opioid-dispensing rate.19 One study compared morphine milligram equivalent (MME) requirements for patients with cancer pain and  found those who also used marijuana had lower MME requirements and had similar pain relief without the dose escalation that is common in opioid pain management.20 The study also reported that 25% of patients taking opioids had less than minimal pain relief; in addition, cancer survivors (even those 10 years in remission) maintained higher opioid prescription rates than those without a diagnosis of cancer.20

In a study of 30 women diagnosed with fibromyalgia, the disease process was resistant to standard pharmacologic interventions. The addition of cannabis improved quality of life, enhanced general health, and improved pain.17,23

 

Six months later, the patient returns to the clinic and is in good spirits. His pain has decreased, and he has decreased his opioid consumption by 25% since his last clinic visit with less associated constipation and hyperalgesia. His sleep has improved with less awakenings from intermittent burning neuropathic pain, and he is able to walk for longer periods of time without having to stop from knee pain. He is interested in learning more about other medically approved cannabinoid medications and their indications as an effort to advocate to his friends and family for their use in medical care without the associated stigma associated with it in the past. A CNN special sparked his interest when he heard that some cannabinoid medications can help patients taking chemotherapy as well as patients with spasticity from neurologic conditions.


You do some reading on medically formulated cannabinoid compounds and get preliminary evidence for the following; dronabinol, nabilone, and nabiximols are cannabinoid-based medications that were formulated to target specific medical conditions. They are distinct from natural cannabis because of their controlled and standardized formulations.14 These synthetic formulations function by interacting with the endocannabinoid system to produce the desired therapeutic effects.

Dronabinol is a synthetic form of THC, and nabilone is also chemically similar to THC. Both are approved for the treatment of anorexia and loss of appetite in patients with AIDS and chemotherapy-induced nausea.4,14 Nabiximols is a whole-plant extract of marijuana and  contains THC and CBD in a 1.08:1.00 ratio. It is administered as an oral mucosal spray. It has been approved for use in Canada and parts of Europe for the treatment of spasticity from MS.5 Studies on dronabinol and its potential use for analgesia have been disappointing due to high incidence of adverse effects at therapeutic doses.14 There have been some case reports of nabilone’s successful use for pain and spasticity associated with MS.14 Epidiolex, an oral and inhaled formulation of CBD, is currently FDA approved for use in the treatment of two severe childhood epilepsy disorders because of its ability to significantly reduce seizure frequency.4

 

Based on the available evidence (Table 1), you tell your patient that although there are a limited number of indications for synthetic cannabinoids that can be medically beneficial, there is currently not sufficient evidence to make strong recommendations for cannabinoid use in treating chronic pain. His case, along with many others in the literature, is a small example of evidence that, when compiled, could lead to stronger recommendations. Currently, the U.S. Drug Enforcement Agency classifies marijuana and natural cannabinoids containing THC as Schedule I drugs, meaning they have no indicated medical use. On a state level, U.S. physicians can make recommendations for the use of medical cannabis for medical conditions; however, they cannot be prescribed. There are a few synthetic cannabinoids formulated for use in specific medical conditions for which prescriptions are available. The future for the role of cannabis and cannabinoids in pain medicine is evolving. The Department of Health and Human Services is recommending that marijuana be moved to a Schedule III drug, which would enable researchers to conduct clinical trials for its use in various medical conditions.

 

The patient states that he now better understands the complexity of the state of investigation of the use of cannabinoids in medicine and is interested in studies in the future that further understand our knowledge of the safety, efficacy, and uses of cannabinoids in chronic pain and other conditions. He plans to return to the clinic in one year and looks forward to learning what new evidence has been discovered at that time. 

Table 1. Review of Literature Detailing Efficacy of Various Compounds

CompoundCytochrome P450 (CYP) System EffectLiterature Detailing Efficacy
Tetrahydrocannabinol  (THC)THC is primarily metabolized by CYP3A4 (thus levels can change with co-administered inducers or inhibitors); may also inhibit CYP3A4.3
  • Delta9-THC is a psychoactive compound, with evidence supporting its use in neuropathic pain. It also has analgesic, anti-inflammatory, antiemetic, and antioxidant properties.1,2,4-8
  • Evidence supports the use of THC in multiple neuropathic pain states, such as diabetic peripheral neuropathy, complex regional pain syndrome, peripheral mononeuropathies, phantom limb pain, HIV-associated peripheral neuropathy, etc.5,8-10,14-17
  • Marijuana was not found to be helpful with postoperative pain scores.5
  • Multiple, induced-pain studies have found marijuana to improve pain tolerance.5 In one of these studies, medium-dose marijuana (4% THC by weight) decreased pain and higher dose (8% THC by weight) increased pain.5
  • Subjects reported improved chemotherapy induced nausea and vomiting (CINV) symptoms after smoking marijuana,5 with comparison groups being either oral THC or placebo.
  • THC was also found to improve pain scores in cancer pain.8
  • Evidence has shown that THC can reduce opioid requirements,5,8,16-19 with patients reporting using cannabis as a substitute for opioids.17,18
  • The addition of cannabis to the medication regimen of a patient with fibromyalgia improved quality of life, enhanced general health, and improved pain.17,23
  • One study gave patients four different potencies of cannabis with post-trauma or postsurgical neuropathic pain; patients reported better sleep and reduced pain as compared to placebo.8
Cannabidiol (CBD)May inhibit CYP2C9, 2C193
  • CBD has anxiolytic, antipsychotic, anti-inflammatory, analgesic, and anticonvulsant properties.1,2,4,6-8
  • CBD is not intoxicating, as compared to THC, and the World Health Organization has labeled it as having “no abuse potential.”5,6 
  • CBD is FDA-approved for seizures in select pediatric epipletic conditions under the brand name Epidiolex.® 
  • CBD may modulate THC,7 widening its therapeutic window and decreasing adverse events.6 
  • CBD has efficacy in the treatment of pain5-7; however, the literature is more limited.2 
  • CBD has preclinical data supporting its use in arthritic conditions.1-2
  • The studied side effects of CBD are more benign than those of THC.4
DronabinolDronabinol is primarily metabolized by CYP2C93
  • Dronabinol is an oral synthetic cannabinoid; brand names include Marinol® and Syndros.®
  • Dronabinol is indicated for CINV treatment or prophylaxis.5 
  • Dronabinol and prochlorperazine together were found to be superior to either medication alone in one study, when treating CINV.5
  • One study found dronabinol ineffective in the treatment of posthysterectomy pain.5 
  • One study found that patients with multiple sclerosis (MS) who took dronabinol perceived their muscle spasms, pain, and sleep to have improved. However, their Ashworth scores did not significantly change.8
  • Another randomized clinical trial investigated dronabinol for MS-associated neuropathic pain and found pain intensities remained at a low level over 32 weeks.16
  • One study of patients with chronic pain who were taking opioids and had dronabinol added to their regimen reported lower pain intensity and “pain bothersomeness.”8 
  • In an induced pain test, dronabinol was compared to smoking marijuana. Both dronabinol and marijuana decreased pain. Dronabinol’s effect lasted longer.24
NabiloneWeak inhibition: CYP2C19, 3A4; moderate inhibition: CYP2C93
  • Nabilone is an oral synthetic cannabinoid. Brand names include Cesamet,TM and Canemes.®
  • Nabilone is indicated for treating chemotherapy-induced nausea and vomiting (CINV) or prophylaxis against CINV.5 
  • Nabilone has been found to be helpful with diabetic neuropathy but not with postoperative pain.5 
  • Case reports detail its successful use for pain and spasticity related to multiple sclerosis (MS).14
NabiximolsSimilar effects as tetrahydrocannabinol (THC) and cannabidiol (CBD), because it is a 1.08:1 ratio of the two compounds3
  • Nabiximols is a phytocannabinoid containing THC and CBD in 1.08:1 ratio. It is administered as an oromucosal spray. The brand name is Sativex.®
  • Nabiximols is approved in Europe and Canada to treat spasticity in MS, but it only available in the United States for clinical trials.5 
  • One study looked at the bioavailability and pharmacokinetics of the oromucosal spray as compared to oral administration and found both to be similar.8 
  • One placebo-controlled, double-blind study found that patients with chronic neuropathic pain had improved pain and sleep over placebo. Patient preference was greatest for THC:CBD over THC or placebo.8
  • Multiple studies detailing improved sleep, pain, and spasticity in those with MS.5-6 
  • One study randomized those with cancer pain resistant to opioid treatment to nabiximols, THC alone, or placebo group. Patients taking nabiximols had improved pain scores over placebo; THC alone did not.5-8 The nabiximols group also had improved insomnia and fatigue.5,8
  • One study did not find that nabiximols helped chemotherapy-induced peripheral neuropathy over placebo.5
  • One study did not find nabiximols improved diabetic neuropathy pain over placebo.5
  • One study found nabiximols helped rheumatoid arthritis pain and sleep better than placebo. 5
  • One study compared nabiximols, THC, and placebo in patients with brachial plexus avulsion injuries. There was not a decreased pain severity score; however, there were statistically significant improvements in pain scores and quality of sleep.8 
  • In a study of 20 patients with MS, spinal cord injury, brachial plexus damage, or limb amputation, patients were given either nabiximols or placebo; those given nabiximols had superior pain relief. 8 
  • One study of 125 patients with allodynia found significantly improved pain scores as compared to placebo.25


References

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  2. Boehnke KF, Clauw DJ. Cannabinoids for chronic pain: translating systematic review findings into clinical action. Ann Intern Med 2022;175:1191-2. https://doi.org/10.7326/M22-1512 
  3. Shah S, Schwenk ES, Narouze S. ASRA Pain Medicine consensus guidelines on the management of the perioperative patient on cannabis and cannabinoids: an infographic. Reg Anesth Pain Med 2023;48:119. https://doi.org/10.1136/rapm-2022-104193 
  4. Urits I, Gress K, Charipova K, et al. Use of cannabidiol (CBD) for the treatment of chronic pain. Best Pract Res Clin Anaesthesiol 2020;34:463-77. https://doi.org/10.1016/j.bpa.2020.06.004 
  5. Kramer JL. Medical marijuana for cancer. CA Cancer J Clin 2015;65:109-22. https://doi.org/10.3322/caac.21260 
  6. Braley TJ, Whibley D, Alschuler KN, et al. Cannabinoid use among Americans with MS: current trends and gaps in knowledge. Mult Scler J Exp Transl Clin 2020;6:2055217320959816. https://doi.org/10.1177/2055217320959816 
  7. Birdsall SM, Birdsall TC, Tims LA. The use of medical marijuana in cancer. Curr Oncol Rep 2016;18:40. https://doi.org/10.1007/s11912-016-0530-0 
  8. Jensen B, Chen J, Furnish T, et al. Medical marijuana and chronic pain: a review of basic science and clinical evidence. Curr Pain Headache Rep 2015;19:50. https://doi.org/10.1007/s11916-015-0524-x 
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  12. Nelson DA, Marks ES, Deuster PA, et al. Association of nonsteroidal anti-inflammatory drug prescriptions with kidney disease among active young and middle-aged adults. JAMA Netw Open 2019;2:e187896. https://doi.org/10.1001/jamanetworkopen.2018.7896 
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  14. Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother 2006;40:251-60. https://doi.org/10.1345/aph.1G217 
  15. Almog S, Aharon-Peretz J, Vulfsons S, et al. The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: A randomized, double-blinded, placebo-controlled trial. Eur J Pain 2020;24:1505-16. https://doi.org/10.1002/ejp.1605 
  16. Petzke F, Tölle T, Fitzcharles M-A, Häuser W. Cannabis-based medicines and medical cannabis for chronic neuropathic pain. CNS Drugs 2022;36:31-44. https://doi.org/ 10.1007/s40263-021-00879-w 
  17. Bell AD, MacCallum C, Margolese S, et al. Clinical practice guidelines for cannabis and cannabinoid-based medicines in the management of chronic pain and co-occurring conditions. Cannabis Cannabinoid Res 2023. https://doi.org/10.1089/can.2021.0156   
  18. Goesling J, DeJonckheere M, Pierce J, et al. Opioid cessation and chronic pain: perspectives of former opioid users. Pain 2019;160:1131-45. https://doi.org/10.1097/j.pain.0000000000001493 
  19. Bao Y, Zhang H, Bruera E, et al. Medical marijuana legalization and opioid- and pain-related outcomes among patients newly diagnosed with cancer receiving anticancer treatment. JAMA Oncol 2023;9:206-14. https://doi.org/10.1001/jamaoncol.2022.5623 
  20. Pawasarat IM, Schultz EM, Frisby JC, et al. The efficacy of medical marijuana in the treatment of cancer-related pain. J Palliat Med 2020;23:809-16. https://doi.org/10.1089/jpm.2019.0374 
  21. Wang L, Hong PJ, May C, et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ 2021;374:n1034. https://doi.org/10.1136/bmj.n1034 
  22. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010;39:167-79. https://doi.org/10.1016/j.jpainsymman.2009.06.008 
  23. Hershkovich O, Hayun Y, Oscar N, et al. The role of cannabis in treatment-resistant fibromyalgia women. Pain Pract 2023;23:180-4. https://doi.org/10.1111/papr.13179 
  24. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology 2013;38:1984–92. https://doi.org/10.1038/npp.2013.97 
  25. Überall MA. A review of scientific evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain. J Pain Res 2020;13:399-410. https://doi.org/10.2147%2FJPR.S240011 


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