Consistent with these observations in other pathologies, cannabinoids may also reduce oxidative stress and pain in SCD.Erythrocyte adhesion, nitric oxide depletion, hemolysis, oxidative stress and inflammation accompany endothelial dysfunction in SCD.Endothelial activation causes upregulation of adhesion molecules including selectins, vascular cell adhesion molecule and intercellular adhesion molecule 1, which exacerbate vaso-occlusion and end-organ damage.CB1R and CB2R are widely expressed on vascular smooth muscle cells and endothelium.Both receptors have been widely studied in vascular relaxation and activation of ion channels including potassium, calcium and TRPVs.Antagonistic roles are demonstrated in different settings and disease states with respect to CB1R and/or CB2R.Thus, it is likely that cannabinoids influence endothelial function in a sickle-specific micro-environment.Cannabis and cannabinoids have been evaluated clinically for their analgesic potential in various disease states, and recently these findings have been described in a systematic review.Studies indicate that smoked cannabis may provide analgesic support in chronic and neuropathic pain, but smoking is associated with its own risks and pathologies; thus, other formulations and routes of administration are also being investigated.To date, several double-blind placebo-controlled studies have been completed to evaluate the safety and efficacy of oral THC and/or Sativex which delivers a controlled dose of 2.7 mg THC and 2.5 mg CBD per spray.Sativex has also been tested in several pain contexts, including cancer, chronic abdominal pain, multiple sclerosis, brachial plexus injury, and diabetic neuropathy.In a study of chronic abdominal pain,container for growing weed oral THC did not reduce measures of pain, but was well-tolerated and absorbed over a 2-month period.
In contrast, Sativex was effective at providing sustained relief of central neuropathic pain in patients with multiple sclerosis on fixed and self-titrating schedules compared to patients receiving placebo.Moreover,Sativex improved pain at targeted responder levels and significantly improved sleep in difficult-to-treat neuropathic pain arising from brachial plexus avulsion and allodynia-characterized neuropathic pain .The latter study was followed-up with a 52-week open-label trial in which pain relief was maintained without dose increase or toxicity.While promising, these studies must be evaluated critically due to their potential for biases related to sampling.Another growing concern is the safety of approaches to alter endocannabinoids, which was most notable with the failed study involving the fatty acid amide hydrolase inhibitor BIA 10-2474.The study was terminated following the death of a patient and irreparable side-effects in other participants.In retrospect, the compound was not as selective of an inhibitor as it was previously believed to be, and early signs of toxicity in pre-clinical studies went ignored.This instance highlights the need for careful, well-controlled pre-clinical studies before undertaking clinical trials.To date, several other clinical studies involving cannabis, THC preparations, and/or Sativex have been completed in patients with chronic pain arising from various diseases.Results from these studies indicate no effect to mild effect at reducing chronic pain, improving sleep quality, and improving patient-reported quality of life.Side-effects from these studies are also limited, and it appears that low doses are well-tolerated.The results from these studies, however, have not undergone peer review, and thus must be heavily scrutinized before any recommendations can be made.The identifiers for the aforementioned studies follow: NCT01606202, NCT00713817, NCT00710424, NCT01606176, NCT01262651, and NCT00241579.Increased access to medicinal cannabis has also shifted open use in SCD patients, with studies reporting greater disease severity and decreased in-patient hospitalizations in patients receiving medicinal cannabis.A cross-sectional study of adults with SCD was performed at the Yale New Haven Hospital, based on patient reported outcomes for pain and health-related quality of life questionnaire using the Adult Sickle Cell Quality of life Measurement Information System to assess VOC pain frequency/severity and impact of pain and Patient-Reported Outcomes Measurement Information System for qualitative assessment of nociceptive and neuropathic pain.
The effect of cannabis on baseline pain and acute pain HRQoL outcomes was examined factoring in for SCD genotype, disease severity, age, gender, genotype, hydroxyurea use, oral morphine equivalents and transfusions, etc.Approximately 20% of SCD subjects reported using cannabis daily compared to 55% non-users and others who used weekly, monthly or in between.Daily users reported significantly higher pain episode severity scores than non-users.However, propensity matched with variables on pain outcomes showed that daily cannabis users reported fewer annual ER visits and annual admissions.Matched for pain impact score for daily pain with other aforesaid variables, daily users had 1.8 and 1.2 fewer annual admissions and ER visits.Similarly, using daily opioids dispensed as a measure of pain matched for other variables showed daily users had 2.5 and 1.5 fewer annual admissions and ER visits compared with others.Since daily users had more severe pain crises, it is inferred that daily use is associated with higher severity of pain crises and that comparisons need to factor in the pain severity and account for other factors such as ability to tolerate pain better.A pilot study performed by our group investigated the analgesic potential of vaporized cannabis in SCD patients.Twenty-three patients with SCD-related chronic pain receiving opioids completed a randomized double-blind placebo-controlled crossover trial, inhaling vaporized cannabis or placebo during two separate five-day inpatient sessions that were separated by a 30-day washout period.Vapors were collected in-house by vaporizing cannabis containing 4.4% THC and 4.9% CBD, obtained from the National Institute on Drug Abuse.The crossover design allowed for each patient to serve as their own control.Pain was assessed throughout each treatment period along with pain interference measures.The crossover-pain difference between cannabis and placebo treatment was negative for each treatment day indicating a decrease in pain with cannabis treatment; however, this decrease was not statistically significant.Additionally, pain levels were generally lower in patients given cannabis when compared to those given placebo, but this difference was also not statistically significant.As each five-day study period progressed, patients given cannabis square pot reported that pain interfered less with activities, including walking and sleeping, with a statistically significant decrease in interference with mood.Importantly, this study showed that vaporized cannabis is well-tolerated and significantly improves “mood” in SCD patients with chronic pain.
The lack of significant adverse effects in this study encourages further investigation into the use of cannabis-based interventions including CBD to treat chronic SCD pain in prospective trials with a larger cohort over a longer duration.Questionnaire-based approaches have provided insight into the prevalence of cannabis use in the SCD community, and these studies have given first-hand accounts of the patients’ perceived benefits and motivations for seeking cannabis.A 2018 survey of 58 patients living with SCD revealed cannabis use in 42% of respondents.The majority of these individuals reported medicinal purposes, though some indicated recreational use of cannabis.The self-reported use further indicates the need to study cannabis to understand its potential risks versus benefits.An anonymous questionnaire study of Sickle Cell patients in the United Kingdom included 31 patients who had used cannabis and 51 patients who had never used it, although this group represents only 34% of individuals that qualified for the study and chose to participate.Responses indicated that cannabis users had more frequent and more severe episodes of pain, but many of the users indicated that cannabis was an attempt at managing their pain.Cannabis users reported improvement in mood , reduced use of painkillers , improvement in feelings of anxiety and depression , and improvement in sleep.In addition, 58% of respondents indicated an interest in participating in future clinical trials for the study of cannabis in SCD pain management.This questionnaire-based study underscores the attractiveness of cannabis as a means of self-medicating for pain, but this also presents another potential concern; to circumvent the prohibition of cannabis, individuals may resort to use of unregulated, potentially dangerous synthetic cannabinoid analogs.Neuropathic pain is disabling and impairs the HRQoL in adolescents as well.In a preliminary study of 12 adolescents with mean age of 15 years, with 75% females and 83% of subjects on hydroxyurea, higher PainDETECT scores were significantly associated with lower PedsQL scores.Cannabis use in teenagers with SCD and cystic fibrosis is prevalent, although to a lower extent than their peers, which may be due to the perception of cannabis use associating with worse self-care, more stress, and more distress.A 2017 retrospective analysis of patients with SCD indicated that patients using cannabis, confirmed by urinalysis, had higher frequency of VOCs.This study comprised 37 SCD patients that tested positive for a THC metabolite and 35 that tested negative.Notably, patients who tested positive admitted to smoking cannabis as their route of administration.Additionally, cannabis users had significantly higher use of benzodiazepine, cocaine, and phencyclidine compared to non-users.The use of other illicit compounds may potentiate the negative effects associated with cannabis use in this retrospective analysis.In addition, cannabis users had significantly fewer visits to the clinic and increased hospital admissions compared to non-users; the lack of regular treatment and increased disease severity may also represent contributing variables that are difficult to control.Priapism, mortality, and other SCD co-morbidities were not different between groups.Opioid-induced hyperalgesia and tolerance to specific opioids has been suggested to lead to cannabinoid and phencyclidine use in an individual with SCD.After switching to morphine, his urine showed the presence of phencyclidine, which provided him better pain relief than morphine.
These studies highlight the inadequacy and changing needs of patients with persistent and/or VOC pain in SCD leading to cannabis use and perhaps of other drugs that they can get to find relief.In a retrospective observational study on 9350 patients 18 years and older admitted for acute ischemic stroke who underwent urine drug screening screening, 18% tested positive for cannabis.Among cannabis users unadjusted risk ratio showed a 50% decrease in risk of AIS.However, upon adjusting for SCD, cardiovascular disease, diabetes, cigarette smoking, ethnicity, age, race, etc., the effect was lost.Many limitations in this study included dosage and duration of cannabis use, but it does not show any adverse effect of cannabis on AIS.These findings are important because stroke is one of the major comorbidities of SCD.A 2016 case study of a sickle cell patient indicated development of acute chest syndrome and failure to modify pain with opioids after the patient had been exposed to the synthetic cannabinoid K2, also known as “Spice”.The patient exhibited delirium and required oxygen support for his first 3 days following hospital admission, after which point the patient admitted to use of K2 at home.The patient’s behavior indicated to the physicians that K2 use was continuing during the hospitalization, and during day 3 acute systolic heart failure was detected.At day 10, the patient was discharged and requested treatment for substance abuse.Use of synthetic drugs labeled cannabinoids share many of the characteristics of intoxication, and also carry risks of dangerous and potentially fatal side effects that include psychosis, seizure, and myocardial infarction.The potency of synthetic cannabinoids derives from their chemical interaction with cannabinoids receptors, for which they are full agonists, whereas THC, the major psychoactive constituent of cannabis, is a partial agonist.These biochemical properties underlie the contrast between synthetic cannabinoids’ apparent toxicity and the lack thereof with THC.The lack of acute toxicity does not mean that THC exposure is without risk.Due to often life-long chronic pain, fear of emerging VOC and rising opioidphobia, SCD patients are more vulnerable to use of cannabis as pain medicine.Cannabis derived cannabinoids have been shown to be safe and well-tolerated in adults across various conditions and, most recently, in SCD.Several studies have indicated mild to moderate effectiveness of cannabis in treating pain arising from various disease states, though heterogeneity and low sample sizes mandate replication.Two major considerations for the use of cannabis products in SCD are pregnancy: the use of cannabinoids has been rising in pregnant women, and in women with SCD this may be a significant concern due to the discontinuation of hydroxyurea during pregnancy.Early preclinical studies provide mixed evidence for the teratogenicity of cannabinoids, so extreme caution must be taken during pregnancy; depression: Volkow et al.reviewed several studies on adverse health effects of recreational cannabis use and found high confidence in the association between cannabis use and addiction to cannabis, symptoms of chronic bronchitis, motor vehicle accidents, and diminished lifetime achievement, as well as medium confidence in its association with abnormal brain development and depression or anxiety.Recent data indicate the prevalence of depression associated with past month’s cannabis use in adults, thus diligent monitoring for the well-being of patients’ physical and mental health is required.The existence of anxiety, depression and cognitive impairment in SCD warrants the need for a close examination of these features in cannabis users.Innumerable medical cannabis preparations are available from “Dispensaries”, but most of them are not validated for their contents and their effectiveness through regulatory analysis and controlled clinical trials, respectively.