scholarly journals Targeting Central Mechanisms of Pain to Improve Acupuncture Analgesia in a Humanized Mouse Model of Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1064-1064
Author(s):  
Ying Wang ◽  
Jianxun Lei ◽  
Kalpna Gupta
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
P38 Mapk ◽  
Central Sensitization ◽  
Cold Sensitivity ◽  
Heat Sensitivity ◽  
Cell Disease ◽  
Opioid Use ◽  
Deep Tissue ◽  
Threshold Increase

Abstract Background: Pain is one of the major comorbidities of sickle cell disease (SCD), which largely remains reliant on opioid use for analgesia. Side effects of opioids including, but not limited to fear of addiction, constipation, pruritus and opioid-induced hyperalgesia warrant the need for analgesic therapies devoid of side effects. Non-pharmacological strategies including acupuncture have been effective in pain treatment. A retrospective analysis (n=24 patients) showed that acupuncture reduced pain in a majority (75%) of SCD patients (Lu K et al., Clin J Pain. 2014). In a mouse model of SCD, electroacupuncture (EA) on conscious free-moving mice led to variable analgesic response ranging from high- (nociceptive threshold increase >200%), moderate- (threshold between 100~200%) to non-responders (threshold increase ≤100%) (Wang Y et al., Sci Rep. 2016). Substance P (SP), a proinflammatory vasoactive neuropeptide in the periphery and centrally and spinal activated p38 mitogen activated protein kinase (MAPK), critical mediators of chronic pain were significantly increased in sickle mice with moderate or no response to EA analgesia. Increased circulating SP has been reported in SCD patients at steady state and during chronic pain. We hypothesize that chronic pain in moderate- and non-responders is due to central sensitization mediated by SP-induced p38 MAPK phosphorylation; and that inhibiting the effect of SP and/or downstream p38 MAPK signaling would improve response to EA in moderate and non-responsive sickle mice. Methods: HbSS-BERK sickle mice expressing human sickle hemoglobin without any treatment and those showing moderate- (threshold between 100~200%) and no-response (threshold increase ≤100%); and HbAA-BERK control mice that express normal human hemoglobin A were used. All groups included mice of both genders at 5-7 months of age and were treated daily with 10 mg/kg, i.p. netupitant (antagonist of neurokinin 1 receptor, a receptor for SP), or SB203580, a p38MAPK inhibitor, with or without four sequential EA treatments (every 3rd day, frequency: 4 or 10 Hz, pulse width: 100 microsecond, duration: 30 min) at acupoint GB30. Hyperalgesia was evaluated daily before starting the inhibitor/EA treatment (baseline, BL) and after treatments throughout 12 days by determining the sensitivity to mechanical-, thermal- and deep tissue-stimuli using von Frey filaments, Hargreaves test, cold plate and grip force, respectively. Results: Sickle mice showing no- or moderate responsive to EA did not demonstrate a significant effect of netupitant or SB203580 without EA on hyperalgesia. However, co-treatment with netupitant and EA reduced mechanical, thermal and deep tissue hyperalgesia through the entire treatment, reaching significance at day 9 and/or day 12. Co-treatment with netupitant enhanced analgesia of EA by significantly decreasing mechanical hyperalgesia (p<0.05 vs untreated sickle or moderate-responder + netupitant) and heat sensitivity (p<0.05 vs BL) at day 9, cold sensitivity (p<0.05 vs BL) at day 12 for both moderate- and non-responders. Deep tissue hyperalgesia for co-treated moderate-responders (p<0.05 vs BL) was significantly reduced at day 9, while the reduction observed with co-treated non-responders (p<0.05 vs BL) only reached significance on day 12. These data suggest that SP mediates sustained chronic pain in SCD, which imparts resistance to EA analgesia. Co-treatment with SB203580 and EA together decreased heat sensitivity (p<0.05 vs BL) at day 9, mechanical hyperalgesia (p<0.05 vs BL or moderate-responder + EA) and cold sensitivity (p<0.05 vs BL) at day 12 and deep tissue hyperalgesia for moderate-responders (p<0.05 vs BL) at day 9 and 12 and non-responders (p<0.05 vs BL) at day 12. Therefore, central sensitization with increased p38MAPK phosphorylation perhaps mediated by high SP levels prevents the responsiveness to EA. Conclusion: Increased SP-induced spinal p38MAPK activation may underlie poor responsiveness to EA and perhaps other analgesic therapies in SCD. Therefore, inhibition of SP or p38 MAPK may improve analgesic outcomes with EA. Circulating SP levels may also be predictive of response to EA and/other analgesic therapies. Co-treatment strategies using acupuncture with mechanism-based targets of central sensitization may be potentially beneficial in treating pain and reducing opioid use in SCD. Disclosures Gupta: Tau tona: Consultancy; Novartis: Honoraria.

Opioid induced hyperalgesia: A focus on opioid use in chronic pain

2013 ◽  
Vol 2 (12) ◽  
pp. 395-397
Author(s):  
Julie L. Cunningham
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
Treatment Option ◽  
Opioid Therapy ◽  
Opioid Use ◽  
Chronic Pain Patients ◽  
Opioid Induced Hyperalgesia ◽  
Pain Patients ◽  
Established Treatment

Opioids are a well-established treatment option for chronic pain. However, opioid therapy is associated with many side effects, including opioid induced hyperalgesia (OIH). This article reviews studies which have evaluated OIH in chronic pain patients on opioids.

Health providers’ perspectives on medical marijuana use.

2017 ◽  
Vol 35 (31_suppl) ◽  
pp. 235-235 ◽  
Author(s):  
Diana Martins-Welch ◽  
Christian Nouryan ◽  
Myriam Kline ◽  
Sony Modayil
Keyword(s):  
Health Care ◽  
Chronic Pain ◽  
Side Effects ◽  
Health Care Providers ◽  
Prescription Drugs ◽  
Medical Marijuana ◽  
The United States ◽  
Care Providers ◽  
Opioid Use ◽  
Cord Injury

235 Background: According to the CDC, 117 million Americans have one or more chronic health conditions and 31% have used two or more prescription drugs in the past month. Approximately 40% of adults in the United States are using some form of Complementary and Alternative Medicine. Medical marijuana is one such medicine, and to date 29 states have legalized medical marijuana. Methods: A multicenter, anonymous, on-line survey of health care providers was distributed via e-mail within a large health system in the NY Metropolitan area. The survey was distributed in April and May of 2017. The specific aim was to collect information about health care providers’ perspectives on the use of MM in general and for specific medical conditions. Results: The sample (n = 137) consisted of 4% RNs, 10% NPs, 10% fellows, 21% resident physicians, and 52% attending physicians. Average experience was 13 years (range: 0-43), half (53%) were under 40 years old and just over half (56%) were female. Most practitioners recognized a benefit of MM for the treatment of cancer-associated symptoms, few were concerned with side effects and 5% of responders answered that MM was not appropriate at any stage of illness. Responders were “most likely to recommend or refer MM if other therapies were not effective” for cancer (83%), chronic pain (68%), spinal cord injury with spasticity (50%), MS (46%), epilepsy (42%), neuropathy (42%) and Parkinson’s disease (41%). Most providers (77%) believed that MM has the potential to reduce overall opioid use, this was found to be statistically more common in younger providers. The most common conditions that providers reported their patients were requesting MM for were cancer (37%), chronic pain (26%) and neuropathy (10%). The most common concerns about MM use were side effects (16%), addiction (13%), legal consequences (11%), cost (7%) and that other providers would judge MM use (7%). Conclusions: Our survey shows that providers are overwhelmingly in support of MM use in patients with chronic illness, particularly in cancer patients. However providers describe significant and practical concerns about MM utilization. Given the rate at which MM is being legalized throughout the country, it is imperative that there be increased focus on education and clinical studies on MM.

Targeting Nociceptin Receptor to Treat Pain in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 373-373
Author(s):  
Derek Vang ◽  
Lucile Vincent ◽  
Katherine NH Johnson ◽  
Nurulaim Zaveri ◽  
Kalpna Gupta
Keyword(s):  
Chronic Pain ◽  
Blood Flow ◽  
Sickle Cell Disease ◽  
Skin Temperature ◽  
Thermal Sensitivity ◽  
Cell Disease ◽  
Mechanical Sensitivity ◽  
Deep Tissue ◽  
And Control ◽  
Nociceptin Receptor

Abstract Abstract 373 Morphine and its congeners remain a sub-optimal approach to treat pain in sickle cell disease (SCD) due to side effects, risk of addiction, and development of tolerance. To avoid these liabilities associated with use of morphine and mu opioid receptor (MOR) agonist analgesics, we examined the ability of nociceptin receptor (NOPR) ligands to treat pain in SCD. The NOPR and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) belonging to the opioid receptor (OR) and opioid family respectively, are involved in nociceptive signaling. Small molecule NOPR agonists are non-addicting, while providing analgesia in acute and chronic pain models. We used AT-200 ([1-(1-cyclooctylpiperidin-4-yl)-indolin-2-one), which has high binding affinity and agonist efficacy at NOPR and low efficacy, partial agonist activity at MOR, to treat chronic and hypoxia/reoxygenation (H/R)-evoked pain, in sickle HbSS-BERK and control HbAA-BERK mice, expressing sickle and normal human hemoglobin, respectively. AT-200 was injected subcutaneously at a dose of 10 mg/Kg. Equal number of mice were treated with vehicle in parallel. Pain behaviors were analyzed over a period of time in the following paradigms [i] under normoxia after a single dose of AT-200, [ii] after injecting AT-200 following the incitement of H/R, and [iii] AT-200 given everyday for 7 days. For comparison, we used 20 mg/Kg morphine treatment following H/R. Pain measures that were characterized included deep tissue pain by grip force measurement, cutaneous hyperalgesia by mechanical sensitivity to von Frey filaments and thermal sensitivity to heat and cold as described by us for sickle mice (Kohli et al., Blood 2010). Blood flow and dorsal skin temperature were measured using laser doppler velocimetry and infrared thermography, respectively. The measure of mechanical threshold and suprathreshold to a 1.0 g von Frey fiber showed a significant reduction in mechanical sensitivity even 24h after AT-200 treatment as compared to vehicle under normoxia (p<0.05 for threshold and p<0.005 for suprathreshold) in sickle mice. H/R evoked a persistent increase in mechanical hyperalgesia in sickle mice up to 24h and in control mice up to 4h, and both were ameliorated by AT-200. Morphine reduced mechanical hyperalgesia following H/R in sickle mice up to 4h but not 24h and its effect was significantly less than that of AT-200. H/R-incitement increased deep pain for 24h in sickle mice and for 30 min in control mice and AT-200 ameliorated both. Interestingly, morphine significantly blocked deep pain at 30 min following H/R (p<0.005), but remained ineffective thereafter in sickle mice. Since deep pain appears is a characteristic feature of vasoocclusive pain in sickle mice as compared to cutaneous pain, it is likely that AT-200 acts as a superior analgesic with a long-lasting effect to treat sickle-specific vasoocclusive pain, compared to morphine. Heat and cold sensitivity were persistently elevated in sickle mice up to 24h post-H/R but returned to baseline (before H/R) in control mice. Both, AT-200 and morphine inhibited the H/R-induced thermal sensitivity up to 24h, in sickle mice, but the effect of AT-200 was significantly more remarkable than morphine. Blood flow and skin temperature increased significantly following H/R in sickle mice (p<0.05 for both vs baseline before H/R) and were significantly reduced by AT-200 and morphine equally, suggesting that both drugs have a similar acute effect on vascular physiology and inflammation in sickle mice. The enhanced analgesic effectiveness of AT-200 compared to morphine, in sickle mice could be due to a ∼2-fold increase in NOPR expression in the dorsal root ganglion of sickle mice compared to control, observed by qPCR in this study. Chronic pain conditions, including pain in sickle mice, are characterized by reduced MOR expression peripherally and in the spinal cord. However, spinal NOPR expression by qPCR did not show a significant difference between sickle and control mice. AT-200 was effective in treating chronic cutaneous, deep tissue and thermal hyperalgesia even after 7 days of continuous treatment without causing tolerance. Thus, AT-200 provided an analgesic effect in chronic pain and that evoked by H/R, without the development of analgesic tolerance in sickle mice. Targeting NOPR appears to be a promising strategy warranting further development of novel NOPR agonists to treat pain in SCD. Disclosures: No relevant conflicts of interest to declare.

Characteristics and Potential Biomarkers for Chronic Pain in Patients with Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 986-986 ◽  
Author(s):  
Nina Kuei ◽  
Niren Patel ◽  
Hongyan Xu ◽  
Leigh Wells ◽  
Latanya Bowman ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Mast Cell ◽  
Sickle Cell Disease ◽  
Substance P ◽  
Cell Activation ◽  
Neurogenic Inflammation ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Opioid Use ◽  
Pressure Pain

Abstract Vaso-occlusive episodes (VOE) or pain crises are a hallmark of sickle cell disease (SCD), with increasing recognition that a significant portion of SCD patients develop chronic pain. In the landmark PiSCES study (Smith et al), patients reported pain on 55% days, with ~30% reporting pain on >90% days. Thus, the episodic, nociceptive pain (VOE) in younger patients, evolves into a chronic pain syndrome, with neuropathic and centralized components in some adults. Kutlar et al (Blood, 2014), reported on the association of different pain related phenotypes (pain diaries, frequency of hospitalizations/ED visits, pressure pain threshold) with polymorphisms in candidate genes in 167 SCD patients, providing evidence that multiple signaling pathways and mechanisms are likely involved. In this study, 12 SCD subjects with "chronic pain", defined by reported pain >50% of days in pain diaries collected over 6 months, were enrolled (SCD-CP). 17 SCD patients who did not have chronic pain (SCD-NCP), and 9 non-SCD African-Americans (C) were enrolled as controls. Informed consent was obtained. Age, gender, Hb F levels, HU usage, and pressure pain algometer readings were recorded from SCD subjects. 8 ml of blood (EDTA) was collected from subjects at "steady state" and from normal controls. Plasma was separated and kept at -80 C until the assay. Plasma tryptase and Substance P levels were assayed by ELISA using kits from Biomatik, Inc. (catalog # EKU07922) and Enzo Life Sciences (Catalog #ADI-900-018), respectively. SCD-CP patients were significantly older than SCD-NCP: mean age 41 vs 32.2 (p=0.033). The pressure pain algometer readings did not differ significantly between SCD-CP and SCD-NCP at three sites (trapezius, ulna, masseter, p= 0.67-0.74). There were 12/17 patients on HU (70.6%) among SCD-NCP, and 6/12 (50%) among SCD-CP (p=0.435). Similarly, Hb F levels were not significantly different (14.7% in SCD-CP, vs 11.7% in SCD-NCP, p=0.446). Opioid use (average morphine equivalent as mg/day) was significantly higher in the chronic pain group (11.45 mg/day, vs 2.92 mg/day, p=0.015). Plasma tryptase and substance-P levels are shown in the table: Table 1. Tryptase (pg/ml) Substance-P (pg/ml) SCD-CP 1388.6 ±519.8 7221.1±7742.7 SCD-NCP 1023.64±221.04 5983.1±3473.0 Control 768.9±416.16 3939.7±1350.1 The difference in substance-P levels did not reach significance across groups by ANOVA (p=0.337) or in pairwise comparison between groups. However, tryptase levels were significantly different across groups by ANOVA (p=0.00615). Pairwise comparisons between two groups showed that tryptase levels were significantly different between SCD-CP and controls (p=0.0053). These results highlight characteristics of SCD patients with chronic pain: they are older, have a higher use of opioids, and have significantly higher tryptase levels. These observations support previous findings that age is a significant factor in transition to chronic pain in SCD. Higher dose of opioid use in SCD-CP could result from dose escalation to control pain; conversely, it could be argued that higher opioid use itself could be a factor in development of chronic pain through opioid-induced hyperalgesia. To our knowledge, this is the first study of plasma tryptase levels in SCD, in relation to different pain phenotypes. Tryptase is released into plasma with degranulation of mast cells and leads to inflammation, anaphylaxis, urticaria, and neuropathic pain. It binds PAR2 (protease activated receptor 2), releasing inflammatory mediators and substance P, inducing neurogenic inflammation. Elevated tryptase levels are found in systemic mastocytosis, and the newly recognized Mast Cell Activation Syndrome (MCAS). Vincent et al (Blood, 2013) showed that mast cell activation played an important role in neurogenic inflammation and chronic pain in a mouse model of SCD. They also demonstrated that inhibition of mast cell activation, via c-kit knockout or with imatinib or cromolyn sodium improved neurogenic inflammation and chronic pain. Two recent case reports (Murphy et al, Stankovic et al) document significant improvement in pain in SCD patients who developed CML, during treatment with imatinib. These observations, and the findings of our pilot study, not only suggest a novel mechanism and biomarker for chronic pain in SCD, but also a potential therapeutic target by inhibition of mast cell activation via c-kit pathway, or stabilization with cromolyn. Disclosures No relevant conflicts of interest to declare.

scholarly journals Daily Associations between Child and Parent Psychological Factors and Home Opioid Use in Youth with Sickle Cell Disease

2019 ◽  
Vol 54 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Amanda L Stone ◽  
Zaria Williams ◽  
Melissa McNaull ◽  
Anna C Wilson ◽  
Cynthia W Karlson
Keyword(s):  
Side Effects ◽  
Sickle Cell Disease ◽  
Negative Affect ◽  
Sickle Cell ◽  
Psychological Factors ◽  
Opioid Analgesics ◽  
Cell Disease ◽  
Opioid Use ◽  
Home Setting ◽  
At Home

Abstract Background Opioid analgesics are frequently used in the home setting to manage episodic pain in youth with sickle cell disease (SCD). Given the risk of adverse side effects, including constipation and sedation, understanding factors associated with at-home opioid use is important for maximizing pain relief while minimizing negative side effects. Purpose The present study aimed to evaluate the relationship between individual psychological factors (pain catastrophizing and negative affect), caregiver psychological factors (catastrophizing about child’s pain and caregiver negative affect), and home opioid use in youth with SCD. Methods Youth with SCD (n = 32) and a caregiver (n = 28) recruited during a routine outpatient hematology visit completed electronic 14 day diaries assessing pain, opioid use, and psychological factors. Results Approximately 28% of youth (n = 9) reported pain ≥50% of diary days and a third of youth (n = 11, 34%) used opioid analgesics at least one of the diary days. The number of days opioid analgesics were used ranged from 0 to 7 (50% of diary days). Results from generalized linear mixed models indicated greater child negative affect accounted for increased odds of opioid use on a given day when accounting for pain intensity. Greater caregiver catastrophizing about children’s pain was also associated with increased odds of children’s opioid use. Conclusions Child and parent psychological factors relate to child opioid use at home for SCD-related pain. Future research is warranted in larger samples to identify targets for interventions to enhance pain management while reducing opioid-related risk and side effects.

scholarly journals Attitudinal Barriers to Analgesic Use among Patients with Substance Use Disorders

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Leah Zallman ◽  
Sonia L. Rubens ◽  
Richard Saitz ◽  
Jeffrey H. Samet ◽  
Christine Lloyd-Travaglini ◽  
...  
Keyword(s):  
Primary Care ◽  
Chronic Pain ◽  
Substance Use ◽  
Side Effects ◽  
Substance Use Disorders ◽  
Opioid Use ◽  
Attitudinal Barriers ◽  
Primary Care Patients ◽  
Opioid Use Disorders ◽  
Analgesic Use

Attitudinal barriers towards analgesic use among primary care patients with chronic pain and substance use disorders (SUDs) are not well understood. We evaluated the prevalence of moderate to significant attitudinal barriers to analgesic use among 597 primary care patients with chronic pain and current analgesic use with 3 subscales from the Barriers Questionaire II: concern about side effects, fear of addiction, and worry about reporting pain to physicians. Concern about side effects was a greater barrier for those with opioid use disorders (OUDs) and non-opioid SUDs than for those with no SUD (OR (95% CI): 2.30 (1.44–3.68), P<0.001 and 1.64 (1.02–2.65), P=0.041, resp.). Fear of addiction was a greater barrier for those with OUDs as compared to those with non-opioid SUDs (OR (95% CI): 2.12 (1.04–4.30), P=0.038) and no SUD (OR (95% CI): 2.69 (1.44–5.03), P=0.002). Conversely, participants with non-opioid SUDs reported lower levels of worry about reporting pain to physicians than those with no SUD (OR (95% CI): 0.43 (0.24–0.76), P=0.004). Participants with OUDs reported higher levels of worry about reporting pain than those with non-opioid SUDs (OR (95% CI): 1.91 (1.01–3.60), P=0.045). Concerns about side effects and fear of addiction can be barriers to analgesic use, moreso for people with SUDs and OUDs.

scholarly journals L-Glutamine Decreases Opioid Use in Individuals with Sickle Cell Disease and Chronic Pain: A Case Series

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4849-4849
Author(s):  
Samuel Wilson ◽  
Frances Wright ◽  
Marcus A. Carden
Keyword(s):  
Chronic Pain ◽  
North Carolina ◽  
Pain Management ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Care Utilization ◽  
Cell Disease ◽  
Opioid Use ◽  
Opioid Prescription ◽  
Over Time

Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States (US), affecting approximately 100,000 individuals in the country who are primarily of African descent. One of the most prevalent complications of SCD is pain as a result of episodic vaso-occlusive crises. Over time, many individuals with SCD develop chronic pain and opioid dependence for pain management. L-glutamine (EndariTM) was approved by the US Food and Drug Administration in 2017 for patients 5 years-old and older to reduce complications from SCD after reviewing a phase-III placebo-controlled trial. In this study, L-glutamine led to a reduction in median number of pain crises and increased time to first pain crisis when compared to placebo (Niihara et al, NEJM, 2018). However, the impact of L-glutamine on opioid use over time remains unknown. In this study, we evaluated the effect on opioid use in individuals who were started on L-glutamine for worsening SCD related pain. Methods: After institutional review board approval, we retrospectively reviewed the electronic medical record (EMR) of individuals with SCD followed at the University of North Carolina Pediatric and Adult Sickle Cell clinics prescribed L-glutamine in 2018-2019 for worsening acute and chronic SCD-related pain. The North Carolina state controlled substance reporting system, an online clinical tool which collects information on dispensed controlled substance prescriptions to patients that is freely available to prescribers, was also reviewed for filled opioid prescriptions (and milligram morphine equivalents - MME) for each patient. Data, including health care utilization (e.g. hospitalizations and emergence room (ER) visits) and hemoglobin levels for each patient were also evaluated in the EMR for the four months preceding and the four months after L-glutamine was started to determine if changes were sustained. Results: We identified four female patients (ages ranging from 9 to 24 years-old) with SS genotype and chronic pain with acute exacerbations who had significant opioid prescription reduction after starting L-glutamine. Three individuals were taking the maximum tolerated dosing of hydroxyurea and experiencing escalating pain crises prior to initiation of L-glutamine. One patient was intolerant of hydroxyurea and was on a chronic transfusion program for chronic pain management when she was started on L-glutamine for worsening chronic pain. All patients, or caregivers, reported a reduction in acute on chronic pain after initiating L-glutamine. Each patient had a reduction in 4-month total opioid prescription use (in MME) after starting L-glutamine, ranging from a 21% reduction to 100% reduction (Figure 1). Heath care utilization significantly decreased in 1 patient after starting L-glutamine, with 3 ER visits and 2 hospitalizations in the pre-treatment period and no ER visits or hospitalizations in the post-treatment period. There was no difference in the average hemoglobin levels pre-and-post L-glutamine initiation among the patients (9.8g/dL vs. 9.7g/dL). Discussion: L-glutamine appears to have some benefit in reducing pain and opioid use, as well as healthcare utilization, in a subset of patients with SCD and chronic pain. Although we evaluated a small number of patients, all individuals (or caregivers) reported decreased pain very soon after starting L-glutamine. One patient stopped opioid use altogether in the time period evaluated. Future studies should investigate if effectiveness of L-glutamine may be based on unique red cell metabolic profiles, SCD genotype, or timing of drug initiation in these and similar patients. Future investigations will also determine long-term tolerability of L-glutamine and if the reduction in opioid use is sustained for longer periods among these patients and other responders. Disclosures Carden: GBT: Honoraria; NIH: Research Funding.

scholarly journals Medical Marijuana for Sickle Cell Disease: Results of Two Years of Certification in an Adult Sickle Cell Center

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 858-858 ◽  
Author(s):  
Susanna A Curtis ◽  
Dana Lew ◽  
Jonathan Spodick ◽  
John D. Roberts
Keyword(s):  
Chronic Pain ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hospital Admissions ◽  
Medical Marijuana ◽  
Marijuana Use ◽  
Cell Disease ◽  
Opioid Use ◽  
Services Utilization ◽  
Admission Rates

Abstract Background: The hallmark of sickle cell disease (SCD) is pain, which can be both acute and chronic. Pain in patients with SCD leads to hospital admissions and diminishes quality of life. Pain in patients with SCD is primarily treated with opioid medications, which are often insufficient. In 2017 the Committee on the Health Effects of Marijuana of the National Academies of Science, Engineering, and Medicine reported that there is "conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of chronic pain in adults", but the report made no mention of chronic pain in patients with SCD. Currently, 30 states and Washington D.C. have medical marijuana (MM) laws, and 5 states list SCD as a qualifying condition. SCD was added to the list of qualifying conditions in Connecticut in February 2016. Since then we have offered certification to patients in our program who make regular clinic visits and for whom we think MM will be safe. However, not all patients who are certified go on to complete the state regulatory paperwork and obtain MM. We hypothesized that those who had obtained MM would show an improvement in clinical outcomes compared to those patients who had been certified but not obtained MM. Methods: All patients who requested certification were educated on safety risks of MM. We conducted a review of all certified patients using our electronic medical record and the Connecticut Prescription Monitoring Program, which provides dispensing reports for schedule I-IV medications including MM. Our primary outcome was admissions in the 6 months after compared to the 6 months before obtaining MM, or the date certified for those who did not obtain MM. Our secondary outcomes were acute care services utilization (emergency department and outpatient infusion center visits) for the treatment of acute pain, and opioid use. Baseline hospital admissions, acute services utilization, and daily opioid use were defined as use in the 6 months prior to obtaining MM or certification for those who did not obtain MM. Opioid use was calculated as total oral morphine equivalents (OME) dispensed in a 6-month period and expressed as OME per day. Previous marijuana use was defined as 1 or more urine studies positive for cannabinoids before MM certification. Genotype was divided into more clinically severe (HbSS/Hbβ0) or less severe (HbSC/Hbβ+/Persistent HbF). We compared admissions, acute services, and opioid use for those who obtained MM to those who did not using a difference in differences analysis. Baseline admissions, baseline acute services, baseline opioid use, age, gender, genotype, hydroxyurea use, previous marijuana use, and insurance type of those who obtained MM were compared to those who did not using Student's t tests. Results: 52 patients requested certification, and 50 patients were certified. 2 patients were not certified due to concerns about inappropriate use based on their past history. Twenty-eight patients who were certified obtained MM; 22 did not. Baseline hospital admissions, acute services utilization, and daily opioid were similar between the two groups. Patients who obtained MM were more likely to be genotype HbSS/HbSβ0. Age, gender, hydroxyurea use, previous marijuana use, and insurance type were similar between the two groups. (Table 1). Patients obtained MM a median of 109.5 days (IQR 54.8 - 188.8) after certification. Two patients concurrently started L-Glutamine within 6 months of MM certification, one who obtain MM and one who did not. Obtaining MM was associated with a decrease in admission rates in the next 6 months compared to those who did not obtain MM (-1.1 admissions 95% CI -0.1 - -2.0, p=0.03). Obtaining MM was not associated with a significant change in acute services utilization (0.3 visits 95% CI -1.4 - 1.9, p=0.8) or daily opioid use (-0.1 OME 95% CI -19.6 - 19.3, p= 1.0). Conclusion: Though there was no difference in admission rates between the two groups we examined prior to MM certification, and the only clinical difference was that those who obtained MM were more likely to be in the moresevere genotype, those who obtained MM showed a decrease in admissions in the next 6 months compared to those who did not. We suggest that MM allowed patients to improve their pain relief and thereby reduce admission rates. This is consistent with data showing cannabinoid agonists improve pain in murine models of SCD. Larger, randomized and controlled studies of MM for pain in SCD should be conducted. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Chronic Opioid Therapy on Pain and Survival in a Mouse Model of Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 726-726
Author(s):  
Varun Sagi ◽  
Huy Tran ◽  
Waogwende Leonce Song-Naba ◽  
Ying WANG ◽  
Aditya M Mittal ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Opioid Therapy ◽  
Cell Disease ◽  
Opioid Use ◽  
Chronic Opioid Therapy ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Pain Characteristics

Abstract Pain is one of the major comorbidities of sickle cell disease (SCD) requiring chronic opioid therapy (COT). However, COT has been associated with reduced survival and opioid-induced hyperalgesia (OIH), which can exacerbate the chronic pain and increased mortality already inherent to SCD. It is challenging to examine pain, opioid use and survival in populations with SCD due to significant heterogeneity in multiple clinicopathologic factors. To determine the effect of COT we used transgenic HbSS BERK sickle mice, which show pain characteristics similar to those observed in patients with SCD, including sensitivity to thermal and mechanical stimuli, increased opioid requirement, and higher levels of circulating substance P and tryptase (Tran et al., Blood 2017). Additionally, similar to female patients with SCD, female BERK sickle mice show more pain than males. Therefore, we performed a randomized double-blind placebo-controlled trial to examine the effect of COT on pain and survival in female homozygous HbSS BERK (sickle) and HbAA BERK (control) mice, expressing >99% human sickle hemoglobin and normal human hemoglobin A, respectively. Mice were injected subcutaneously each day with either morphine sulfate at a starting dose of 20 mg/kg, which was increased to 25 mg/kg, 30 mg/kg, 35 mg/kg, and 40 mg/kg after weeks 12, 18, 28, 30, and 38 respectively or placebo (equal volume of saline) until the end of survival. Dose of morphine was selected based on the effective analgesic dose for these mice (Kohli et al., Blood 2010). Mechanical-, thermal- (heat and cold), and musculoskeletal/deep hyperalgesia were analyzed in all mice biweekly before and after drug treatments. We used Kaplan-Meier and log-rank test with Sidak correction for survival; 2-way repeated measures analysis of variance with Bonferroni's correction to compare hyperalgesia between time points among control and sickle mice and Cox proportional-hazards regression analysis for the association of hyperalgesia with survival. We observed significantly decreased survival of saline-treated sickle mice compared to saline-treated control mice (P = 0.0009). Compared to saline, morphine treatment led to a significant decrease in survival in control mice (P = 0.035) but not in sickle mice (P > 0.05). Furthermore, we did not observe an association between hyperalgesia and survival in either control or sickle mice. However, we discerned a significant increase in mechanical, cold, and heat hyperalgesia in control mice after 4 weeks of morphine treatment (P < 0.02, compared to day '0') which continued to increase up to 12 weeks (P <0.05 compared to week 4). Similarly, in sickle mice we observed an increase in mechanical hyperalgesia after 4 weeks (P <0.02, compared to day '0') of morphine treatment which continued to increase up to 12 weeks (P < 0.0001). These data suggest COT leads to OIH in both control and sickle mice. It is noteworthy that morphine treatment continued to show an analgesic effect over the course of 12 weeks in spite of an increase in hyperalgesia in both groups of mice. Thus, mice did not develop tolerance to morphine analgesia. Since mice were treated under uniform conditions, the effect of chronic morphine treatment could be observed without any confounding factors. Our findings in control mice recapitulate the clinical observations that COT is associated with reduced lifespan in non-sickle patients. COT lead to OIH in sickle mice but provided analgesia without causing tolerance or reducing survival. OIH may contribute may exacerbate a vicious cycle of chronic pain and opioid use in SCD. Differences exist between humans and mice including morphine metabolism between the two but due to several similarities of HbSS BERK sickle mice with clinical pain characteristics and biology, these observations have a significant translational potential following clinical trials for optimizing the treatment of pain in SCD. These data highlight the critical need to develop analgesic strategies devoid of OIH. Disclosures Gupta: Tau tona: Consultancy; Novartis: Honoraria.

Mechanisms of pain in sickle cell disease

2020 ◽  
pp. 204946372092068 ◽  
Author(s):  
Kensuke Takaoka ◽  
Asha Caroline Cyril ◽  
Sandhya Jinesh ◽  
Rajan Radhakrishnan
Keyword(s):  
Chronic Pain ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Central Sensitization ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
The Novel ◽  
Cell Disease ◽  
Disease Mechanisms ◽  
Tissue Injuries

Objectives: The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. Methods: We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. Results: Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. Discussion: In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.

Sign in / Sign up

Export Citation Format

Share Document