Clinical pain management with opioids is presented in another review in this Special Issue and is thus not discussed in detail herein.Cannabinoids represent a promising alternative due to their tolerability and pre-clinical evidence for their efficacy in attenuating chronic and acute hyperalgesia in SCD.A recent prospective clinical trial of vaporized cannabis use in SCD also shows promise for cannabinoid use without any significant adverse events.Hence, we discuss the mechanism-based understanding of using cannabinoids to treat pain based on pre-clinical and clinical observations in SCD.More importantly, we critically review the benefits and risks of cannabis use in the current environment flooded with “Medical Cannabis” and uncontrolled availability of cannabis products over the counter.We have used the word cannabis when cannabis has been used and cannabinoids as a general term for products derived from cannabis or synthetic cannabinoids.Cannabinoids comprise a broad class of plant-derived, synthetic, and endogenously produced compounds that act via cannabinoid receptors 1 and 2 and possibly others.The major plant-derived cannabinoids from Cannabis sativa L.are ∆9 -tetrahydrocannabinol and Cannabidiol.There also exists a class of endogenously produced cannabinoids, dubbed endocannabinoids ; the major eCBs are anandamide and 2-arachidonoyl-sn-glycerol , which are lipid-based signaling molecules that are produced on-demand.There has been a cascade of synthetic cannabinoids that act with higher potency than plant-derived and endogenous cannabinoids, which are invaluable research tools though many have potential for abuse.The eCB system comprises the cannabinoid receptors, their endogenous ligands—the eCBs—and corresponding biosynthetic and degradative enzymes.Emerging strategies for leveraging the eCB system in various models of pain include targeting the enzymes responsible for production and breakdown of eCBs.The intoxicating effects of THC are mediated through activation of CB1R,marijuana grow system which are concentrated in the central nervous system and are also expressed diffusely throughout the mammalian body.
CB1R activation has been shown to modulate pain, appetite, cognition,emesis, reward , neuroexcitability, balance, thermoregulation and motor function.CB2R are expressed primarily on immune cells and display roles in regulating responses to pain, immune challenge, inflammation, and cell proliferation.CBD has been suggested to act via modulation of CB1R and/or other mechanisms, and we have previously discussed CBD for use in chronic pain.SCD originates from a single point mutation of the beta globin gene of hemoglobin that leads to rigid sickle-shaped red blood cells in a deoxygenated state.The biological underpinnings of pain in SCD remain poorly understood.Pain in SCD may be a direct consequence of avascular necrosis or lower limb ulcers.It is known that sickle RBCs cause vaso-occlusion leading to impaired blood and oxygen supply to the organs resulting in end-organ damage and acute, unpredictable and recurrent episodes of pain.Inflammation, endothelial activation, oxidative stress, ischemia/reperfusion injury, and hemolysis underlie sickle pathobiology, which are further enhanced in the wake of VOCs.The underlying mechanism for how vaso-occlusion leads to pain remains incompletely understood.In the last decade, strong pre-clinical findings have characterized chronic pain and the underlying key mechanisms that cause it.These include neurogenic and neuro inflammation, activation of transient receptor potential vanilloid 1, peripheral nerve damage, peripheral and central sensitization, spinal glial activation, increased blood–brain barrier permeability, mast cell activation, and Purkinje cell damage in the cerebellum.Neuroinflammation demonstrated with increased circulating substance P and glial fibrillary acidic protein and central sensitization have also been observed clinically.Dorsal horn neurons in preclinical sickle models also demonstrated higher excitability in concert with activation of signaling pathways that promote neuronal excitability with increased GFAP-expressing astroglial cells and microglial activation.Therefore, humanized mouse models of SCD have provided mechanistic insights that mimic key features and mechanisms of pain observed clinically.The discovery of pain mediation by mast cells was the foremost demonstration of neuroimmune interactions affecting sickle pain.Inflammation and neuroinflammation arising from increased glial, neutrophil, monocyte, mast cell and neural activation and neurogenic inflammation underlie nerve injury leading to neuropathic pain, which may present non-uniformly in sickle patients as suggested by quantitative sensory testing.
Hypersensitivity and lower threshold to mechanical and thermal stimuli on QST in patients with SCD may be due to injury to the peripheral and/or central nervous system, evoked by neuroinflammatory substances such as SP .Sickle patients have higher plasma levels of SP, tryptase and GFAP, markers of neuroinflammation.Tryptase is released from mast cell activation and sickle patients with acute myeloid leukemia benefited from mast cell inhibitor imatinib treatment exhibited by amelioration of VOC.In our preclinical studies, inhibiting mast cell activation with imatinib elicited significant analgesic response along with reduced expression of SP/calcitonin gene-related peptide , systemic inflammation, neurogenic inflammation and neuroinflammation.Our results indicated that activated mast cells in sickle micro-environment release tryptase eliciting SP and CGRP from peripheral nerve endings.Vasoactive SP and CGRP lead to neurogenic inflammation by stimulating vascular permeability in sickle mice.Persistent mast cell activation in a feed-forward loop orchestrated by SP and other inflammatory mediators may contribute to the sustained sensitization of the peripheral nociceptors and consequently spinal neurons.Cannabinoids have been shown to inhibit mast cell activation, and therefore have the potential to ameliorate sickle pain and VOC.Stress-induced neuroinflammation was significantly attenuated in wild-type mice treated with JWH-133 and mice over expressing CB2R, but not in CB2R-knockout mice.Therefore, CB2R agonists augment CB1R analgesia in sickle pain, and both may be required to achieve effects similar to those from whole plant-based compounds found in cannabis.Cannabinoids attenuate inflammation, leukocyte trafficking and adhesion, mast cell activation, oxidative stress, ischemia/reperfusion injury and neurogenic inflammation via CB1Rs and CB2Rs.All these phenomena exacerbate pain and may underlie clinical features of SCD including impaired wound healing, renal damage, and retinopathy .Our finding that CP55,940 reduces hyperalgesia was associated with reduced mast cell activation, leukocyte counts and neurogenic inflammation.Severe inflammation in SCD is characterized by elevated cytokines, pro-inflammatory and vasoactive neuropeptides, in both humans and sickle mice.Microglial activation with significantly higher cytokine levels, toll-like receptor 4 expression and Stat3 phosphorylation in sickle mice spinal cords suggest a central inflammatory milieu.
In animal models of diverse diseases, CB2R was found to mediate the anti-inflammatory effect of cannabinoids such as CBD, HU210, and WIN55,212-2, both peripherally and centrally.THC exhibits an anti-inflammatory effect that is mediated primarily through CB1Rs; however, CB2Rs do appear to play a critical role in regulating inflammation in most cellular and animal studies.Therefore, cannabinoids have the potential to target many mechanisms underlying pain in SCD and other comorbidities.Inflammation, hemolysis, and cell-free hemoglobin in the hypoxic sickle microenvironment cause oxidative stress in SCD.WIN55,212-2, CP55,940 and anandamide exert a protective effect on quinolinic acid-induced mitochondrial dysfunction, reactive oxygen species formation and lipid peroxidation in rat striated cultured cells and rat brain synaptosomes .Importantly, in parkin-null, human tau over expressing mice, a model of complex neurodegenerative disease, short-term Sativex administration significantly reduced intraneuronal monoamine oxidase-related free radicals, increased the ratio of reduced/oxidized glutathione, and improved behavioral and pathological abnormality.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, 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 vertical farming, 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 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.